Conditions: HER2-amplified Biliary Tract Cancers
Keywords: HER2 Bispecific antibody Biparatopic antibody Immunotherapy Biliary Tract Cancer Intra-hepatic cholangiocarcinoma Extra-hepatic cholangiocarcinoma Gallbladder cancer JZP598
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 87
Healthy volunteers: no

Brief summary:
This multicenter, open-label, single-arm trial will evaluate the anti-tumor activity of ZW25 (zanidatamab) monotherapy in subjects with human epidermal growth factor receptor 2 (HER2)-amplified, inoperable and advanced or metastatic biliary tract cancer (BTC), including intra-hepatic cholangiocarcinoma (ICC), extra-hepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC).

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: ZW25 (Zanidatamab)
Intervention descriptions: intervention 1: Administered intravenously

Protocol document:
Prot_000.pdf: 
Protocol Number: 
ZWI-ZW25-203 
Version: 
Amendment 3; 08 September 2023 
Protocol Title: 
A Phase 2b, open-label, single-arm study of zanidatamab (ZW25) 
monotherapy in subjects with advanced or metastatic HER2-amplified 
biliary tract cancers 
Study Short Name: 
HERIZON-BTC-01 
Investigational Drug: 
zanidatamab (ZW25, JZP598) 
Phase: 
2b 
IND Number: 
 
EudraCT Number: 
2020-000459-11 
EU CT Number: 
2023-508134-34-00 
Sponsor (Rest of World): 
Jazz Pharmaceuticals Ireland, Limited 
Waterloo Exchange, Waterloo Road 
Dublin 4, Ireland 
US Sponsor 
Representative: 
Jazz Pharmaceuticals, Inc 
3170 Porter Drive  
Palo Alto, CA 94304  
Sponsor (China and South 
Korea): 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
2955 Campus Drive, Suite 200 
San Mateo, CA 94403 
USA 
BeiGene (Beijing) Co., Ltd, 
Room 101, 201, 402, 502, 
Building 1, No. 30 Science Park 
Road, Changping District, 
102206, Beijing, China 
Medical Monitor (Rest of 
World): 
 MD, PhD 
Jazz Pharmaceuticals, Inc 
Sr. Medical Director 
Contact information appears in the trial site binder (or equivalent) 
Medical Monitor (China 
and South Korea): 
 MD 
BeiGene, Ltd 
Senior Physician 
Clinical Development 
Tel: 
 
Confidentiality Statement 
The information contained in this document is the property of Jazz Pharmaceuticals Ireland, Limited (Jazz 
Pharmaceuticals) and is confidential. This information is provided to you in confidence as an investigator, 
potential investigator, or consultant for review by you, your staff, and an Institutional Review Board or 
Independent Ethics Committee. The information is only to be used by you in connection with clinical studies of 
the investigational product described in the study protocol. This document may not be reproduced, published, or 
disclosed to others without written authorization from Jazz Pharmaceuticals. except to the extent necessary to 
obtain informed consent from persons to whom the investigational product may be administered. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023  
ZWI-ZW25-203 
Amendment 3 
Page 2 of 97  
 
 
Confidential 
 
 
PROTOCOL SYNOPSIS 
Protocol Number 
ZWI-ZW25-203 
Version 
Amendment 3; 08 September 2023 
Phase 
2b 
Product Name 
zanidatamab (ZW25, JZP598) 
Sponsor 
Jazz Pharmaceuticals Ireland, Limited  
Waterloo Exchange, Waterloo Road 
Dublin 4, Ireland  
 
US Sponsor Representative:  
Jazz Pharmaceuticals, Inc 
3170 Porter Drive 
Palo Alto, CA 94304 
 
Protocol Title 
A Phase 2b, open-label, single-arm study of zanidatamab (ZW25) monotherapy in subjects with 
advanced or metastatic HER2-amplified biliary tract cancers 
 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary: 
● To evaluate the anti-tumor activity of 
zanidatamab monotherapy in subjects with 
advanced or metastatic HER2-amplified biliary 
tract cancers (BTC) 
● Confirmed objective response rate (ORR) by the 
Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1), assessed by 
independent central review (ICR) 
Secondary: 
● To further evaluate the anti-tumor activity of 
zanidatamab monotherapy in subjects with 
advanced or metastatic HER2-amplified BTC 
● Duration of response (DOR) by RECIST 1.1 
assessed by ICR 
● Proportion of subjects with a DOR ≥ 16 weeks by 
RECIST 1.1 assessed by ICR 
● Disease control rate (DCR) by RECIST 1.1 
assessed by ICR 
● Progression-free survival (PFS) by RECIST 1.1 
assessed by ICR 
● ORR by RECIST 1.1 assessed by investigator 
● DOR by RECIST 1.1 assessed by investigator 
● Proportion of subjects with a DOR ≥ 16 weeks by 
RECIST 1.1 assessed by investigator 
● DCR by RECIST 1.1 assessed by investigator 
● PFS by RECIST 1.1 assessed by investigator 
● Overall survival (OS) 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023  
ZWI-ZW25-203 
Amendment 3 
Page 3 of 97  
 
 
Confidential 
 
 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Secondary (Cont.): 
● To evaluate the safety and tolerability of 
zanidatamab monotherapy in subjects with 
advanced or metastatic HER2-amplified BTC 
● Frequency and severity of adverse events (AEs) 
● Frequency of serious adverse events (SAEs) and 
deaths 
● Frequency and severity of clinical laboratory 
abnormalities 
● Frequency of dose modifications of zanidatamab 
● To evaluate the pharmacokinetics (PK) of 
zanidatamab 
● Serum concentrations of zanidatamab as a 
function of time post-dosing 
● PK parameters for single (first) dose and multiple 
doses 
● To evaluate the immunogenicity of zanidatamab 
● Frequency, duration, and time of onset of anti-drug 
antibodies (ADA) and neutralizing antibodies, if 
applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design 
This pivotal, multicenter, open-label, single-arm trial will evaluate the anti-tumor activity of zanidatamab 
monotherapy in subjects with HER2-amplified, inoperable and advanced or metastatic BTC, including intra-
hepatic cholangiocarcinoma (ICC), extra-hepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC). 
Subjects must have received at least 1 prior gemcitabine-containing systemic chemotherapy regimen for advanced 
disease, and have experienced disease progression after or developed intolerance to the most recent prior therapy. 
New or archival tumor tissue is required from all subjects for HER2 amplification and HER2 protein expression 
testing at a central lab using in situ hybridization (ISH) and immunohistochemistry (IHC) assays. Subjects may 
be tested for HER2 status at the central lab any time after diagnosis of advanced or metastatic disease and 
before study enrollment. Subjects who elect to be pre-screened for HER2 status must sign a separate informed 
consent for collection, storage, and analysis of the tumor tissue. Once a prospective subject experiences disease 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023  
ZWI-ZW25-203 
Amendment 3 
Page 4 of 97  
 
 
Confidential 
 
 
progression or develops intolerance to his/her most recent prior therapy, the main consent for the remaining 
screening assessments must be signed. 
Two cohorts of subjects will be enrolled: 
• 
Cohort 1, comprising subjects with HER2 amplification by ISH and HER2 overexpression by IHC; 
i.e., IHC 2+ or 3+ 
• 
Cohort 2, comprising subjects with HER2 amplification by ISH and HER2 IHC 0 or 1+ 
Enrolled subjects will receive zanidatamab, 20 mg/kg given intravenously (IV) every 2 weeks (Q2W) until 1 of 
the treatment discontinuation criteria is met. The primary endpoint of confirmed ORR per RECIST 1.1 will be 
evaluated by ICR. Disease response will be evaluated every 8 weeks (Q8W) using computed tomography (CT) 
or magnetic resonance imaging (MRI) scans. 
Number of Planned Subjects 
Cohort 1: approximately 75 subjects. 
Cohort 2: approximately 25 subjects. 
Study Population 
Subjects must meet the below enrollment criteria to be eligible for this study. Eligibility criteria may not be 
waived by the investigator and are subject to review in the event of a Good Clinical Practice (GCP) audit 
and/or health regulatory authority inspection. 
Inclusion Criteria 
1. 
Histologically- or cytologically-confirmed BTC, including ICC, ECC or GBC. 
2. 
Locally advanced or metastatic BTC and not eligible for curative resection, transplantation, or 
ablative therapies. 
3. 
Received at least 1 prior gemcitabine-containing systemic chemotherapy regimen for advanced disease, and 
experienced disease progression after or developed intolerance to the most recent prior therapy. For 
subjects who received gemcitabine in prior adjuvant or neoadjuvant treatment, if progression occurred 
< 6 months from the latter of primary surgical resection or completion of gemcitabine-containing adjuvant 
therapy, they will be considered as having received 1 prior line of therapy for advanced disease. 
4. 
Subjects must have at least 1 measurable target lesion by RECIST 1.1. Subjects who have received prior 
local therapy (embolization, chemoembolization, radiofrequency ablation, or radiation therapy) are eligible 
provided measurable disease falls outside of the treatment field or is within the treatment field and has 
shown ≥ 20% growth in size since post-treatment assessments. 
5. 
Subjects must test positive for HER2 amplification by in situ hybridization (ISH) assay at a central 
laboratory on a new biopsy or archival tissue. Note that fine needle aspirates (FNAs; cytology samples) 
and biopsies from sites of bone metastases are not acceptable. Testing may occur at any time after 
diagnosis of advanced or metastatic disease and before study enrollment. 
6. 
Male or female, ≥ 18 years of age (or the legal age of adulthood per country-specific regulations). 
7. 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023  
ZWI-ZW25-203 
Amendment 3 
Page 5 of 97  
 
 
Confidential 
 
 
8. 
Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count 
≥ 75 x 109/L (not requiring transfusion support), and hemoglobin (Hgb) ≥ 9 g/dL (subjects with chronic 
anemia that is supported by intermittent red blood cell [RBC] transfusions are eligible). 
9. 
Liver function: serum bilirubin ≤1.5 x the upper limit of normal (ULN) or ≤3 x ULN for subjects with 
Gilbert’s disease, aspartate aminotransferase (AST) ≤ 3 x ULN, and alanine aminotransferase (ALT) ≤ 3 x 
ULN. For subjects with liver involvement, AST, and ALT ≤ 5.0 x ULN is acceptable. 
10. Adequate cardiac function, as defined by left ventricular ejection fraction (LVEF) ≥ 50%. 
11. Kidney function: glomerular filtration rate (GFR) ≥ 30 mL/min as estimated by the Modification of 
Diet in Renal Disease (MDRD) equation (see Section 7.8.3). 
12. Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin 
(β-hCG) pregnancy test result within 3 days prior to the first dose of zanidatamab. Females with false 
positive urine test results can be enrolled if subsequent serum testing is negative (see Section 4.3). 
13. For female subjects of childbearing potential and for male subjects with a partner of child-bearing 
potential, willingness for the couple to use 2 methods of birth control with a failure rate of less than 1% per 
year during the study and for 12 months after the last dose of zanidatamab (see Section 4.3). 
14. Male subjects must agree to not donate sperm and female subjects must agree to not donate oocytes 
starting at screening and throughout the study period, and for at least 12 months after the last dose of 
zanidatamab (see Section 4.3). 
15. The subject or subject’s legally acceptable representative must provide written informed consent. Subjects 
who elect to be pre-screened for HER2 status must provide a separate written informed consent for 
collection, storage, and analysis of the tumor tissue. 
Exclusion Criteria 
1. 
Received systemic anti-cancer therapy within 3 weeks of the first dose of zanidatamab. Received 
radiotherapy within 2 weeks of the first dose of zanidatamab. 
2. 
Had major surgery within 4 weeks of the first dose of zanidatamab. 
3. 
Prior treatment with HER2-targeted agents. 
4. 
Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation treatment 
for CNS metastases within 4 weeks of start of study treatment. Stable, treated brain metastases are allowed 
(defined as subjects who are off steroids and anticonvulsants and are neurologically stable with no evidence 
of radiographic progression for at least 4 weeks at the time of screening). 
5. 
Known leptomeningeal disease (LMD). If LMD has been reported radiographically on baseline MRI, but is 
not suspected clinically by the investigator, the subject must be free of neurological symptoms of LMD. 
6. 
Concurrent uncontrolled or active hepatobiliary disorders or untreated or ongoing complications after 
laparoscopic procedures or stent placement, including but not limited to active cholangitis, unresolved 
biliary obstruction, infected biloma or abscess. Any complications must be resolved more than 2 weeks 
prior to the first dose of zanidatamab. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023  
ZWI-ZW25-203 
Amendment 3 
Page 6 of 97  
 
 
Confidential 
 
 
7. 
Prior or concurrent malignancy whose natural history or treatment has, in the opinion of the 
investigator or medical monitor, the potential to interfere with the safety or efficacy assessment of 
the investigational regimen. 
8. 
Significant acute infection or chronic infections that have not stabilized with treatment. 
9. 
Active hepatitis, including the following: 
a. 
Acute or chronic hepatitis B (Exception: subjects who are hepatitis B surface antigen positive 
are eligible if they have HBV DNA less than 500 IU/mL) 
b. 
Infection with hepatitis C (Exception [i] subjects who have no history of curative viral treatment 
and are documented to be viral load negative are eligible; [ii] subjects who have completed 
curative viral therapy ≥ 12 weeks prior to enrollment, and viral load is negative are eligible) 
10. Infection with human immunodeficiency virus (HIV)-1 or HIV-2 (Exception: subjects with well-controlled 
HIV [e.g., CD4 > 350/mm3 and undetectable viral load] are eligible). 
11. Females who are breastfeeding or pregnant, and females and males planning a pregnancy. 
12. History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or 
excipients in the drug formulation of zanidatamab. 
13. Treatment with anthracyclines within 90 days before first dose of zanidatamab and/or total lifetime load 
exceeding 360 mg/m2 Adriamycin® or equivalent. 
14. Use of corticosteroids administered at doses equivalent to > 15 mg per day of prednisone within 2 weeks of 
first zanidatamab dosing unless otherwise approved by the medical monitor. Topical, ocular, intra-articular, 
intranasal, and/or inhalational corticosteroids are permitted. 
15. Ongoing, clinically significant toxicity (Grade 2 or higher) associated with prior cancer therapies, with 
the following exceptions: 
a. 
Alopecia 
b. 
Congestive heart failure (CHF), which must have been ≤ Grade 1 at the time of occurrence and 
which must have completely resolved 
c. 
Grade 2 peripheral sensory neuropathy 
16. QTc Fridericia (QTcF) > 470 ms. 
17. History of myocardial infarction or unstable angina within 6 months prior to enrollment, troponin levels 
consistent with myocardial infarction, or clinically significant cardiac disease, such as ventricular 
arrhythmia requiring therapy, uncontrolled hypertension, or any history of symptomatic CHF. 
18. Acute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver disease. 
19. Any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact 
safety or compliance with study procedures. 
Test Product, Dose, and Mode of Administration 
Zanidatamab (ZW25), 20 mg/kg, given IV Q2W (Days 1 and 15 of each 28-day cycle). 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023  
ZWI-ZW25-203 
Amendment 3 
Page 7 of 97  
 
 
Confidential 
 
 
Reference or Combination Products, Dose, and Mode of Administration 
N/A. 
Required Premedication 
All subjects must receive mandatory prophylactic treatment for potential infusion reactions 30 to 60 minutes 
before the start of each zanidatamab infusion. Pretreatment should include corticosteroids, antihistamines, and 
acetaminophen at the following recommended doses: 
● Corticosteroids - either hydrocortisone 100 mg IV or dexamethasone 10 mg IV 
● Antihistamines - diphenhydramine 50 mg per oral (PO) or IV 
● Acetaminophen - 650 to 1000 mg PO 
If an alternative premedication regimen is thought to be required, the investigator must seek sponsor 
approval. Sponsor approval is required before implementation. 
For subjects who experience an infusion reaction despite the above premedications, other medication(s) as 
needed per the investigator or per institutional standards including histamine-2 receptor antagonists (H2 
blockers) may be given in addition to the mandatory premedication. 
Duration of Treatment 
Subjects may continue on treatment with zanidatamab until investigator-determined radiographic disease 
progression per RECIST 1.1, unequivocal clinical progression, unacceptable toxicity, consent withdrawal, 
physician decision, pregnancy, start of a subsequent anticancer therapy, or study termination by the sponsor. 
Unequivocal clinical progression is defined as worsening or re-emergence of pre-existing symptoms relating to 
underlying cancers (e.g., increase in disease-related pain), or emergence of new symptoms that cannot be 
attributed to study drug toxicities or alternative causes. A marked deterioration in ECOG performance status 
may also indicate unequivocal clinical progression. Every effort should be made to confirm disease progression 
radiographically. Only in instances where subjects appear to have unequivocal clinical progression and it is not 
possible or feasible for the subject to undergo radiologic assessment should investigators remove the subject 
from study treatment. Subjects who discontinue treatment with zanidatamab for any reason should enter the 30-
day safety follow-up period, and will continue with efficacy follow-up (if treatment discontinuation was due to 
reasons other than progressive disease or start of subsequent anticancer therapy) as well as survival follow-up. 
Efficacy Assessments 
CT and/or MRI scans will be performed at baseline and Q8W during treatment (timed from Cycle 1 Day 1) and 
will continue after treatment discontinuation every 8 weeks until disease progression or start of subsequent 
anticancer therapy. Disease response will be assessed according to RECIST 1.1 by ICR (primary endpoint) and 
investigator (secondary endpoint); responses are to be confirmed 4 weeks following initial documentation of 
objective response by the investigator. 
Pharmacokinetic and Immunogenicity Assessments 
Blood samples will be collected at protocol-specified timepoints for evaluation of serum concentrations 
(PK) of zanidatamab and for evaluation of ADA (immunogenicity). 
Serum concentrations of zanidatamab will be measured as a function of time post-dosing. PK parameters to be 
estimated include the following: 1) for single (first) dose: maximum concentration (Cmax), time to maximum 
concentration (tmax), area under the serum concentration-time curve from zero to the last measurable 
concentration (AUC0-t), terminal elimination rate constant (λz), half-life (t1/2), area under the serum 
concentration-time curve from zero to infinity (AUC0-∞), serum clearance (CL), volume of distribution (Vd), etc. 
and 2) for multiple doses: area under the serum concentration-time curve from zero to the end of dosing interval 
(AUCtau), average concentration (Cave) for Dose 1, Cmax and minimum concentration (Cmin) (trough) for 
subsequent doses, accumulation index, fluctuation ratio, steady state concentration (Css), and attainment of steady 
state. ADAs to zanidatamab and possibly neutralizing antibodies will be measured, including frequency, time of 
onset, and duration of immunogenicity response. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023  
ZWI-ZW25-203 
Amendment 3 
Page 8 of 97  
 
 
Confidential 
 
 
At least 30 subjects (the first 10 subjects enrolled in China and first 20 suitable subjects enrolled in the rest of 
world) will be assigned to an extensive PK schedule (suitability determined by the medical monitor). Further 
subjects will then be assigned to the sparse PK schedule (peak-trough measurements only). Thirty subjects (the 
first 10 suitable subjects in China who reach Cycle 4 and first 20 suitable subjects in the rest of the world who 
reach Cycle 4, with suitability determined by the medical monitor) will also be assigned to an extensive PK 
schedule for 1 cycle at steady state (Cycle 4 or later). 
Biomarker Assessments 
Blood and tumor tissue samples will be collected at the specified timepoints for assessment of biomarkers. 
Biomarkers may include but are not limited to circulating tumor DNA (ctDNA), tumor tissue DNA and RNA, 
HER2 extracellular domain (ECD), carbohydrate antigen 19-9 (CA19-9), and post-treatment HER2 tumor 
status. Biomarkers will be investigated as an exploratory endpoint and will not be used to guide subject 
selection for the study. Only the biomarkers specified above will be tested on samples collected in Mainland 
China. 
Safety Assessments 
Safety will be monitored by recording the type, frequency, and severity of AEs, including the following: 
● Adverse events of special interest (AESIs): infusion-related reactions, non-infectious pulmonary 
toxicities, and cardiac events of absolute decrease in LVEF of ≥ 10 percentage points from 
pretreatment baseline and absolute value < 50%, and/or grade ≥ 2 heart failure 
● SAEs and deaths 
The following safety parameters will also be assessed: 
● Clinical laboratory values (including hematology, coagulation, serum chemistry, and urinalysis) 
● Physical examination 
● Vital signs (blood pressure, heart rate, respiratory rate, and temperature) 
● ECOG PS 
● Concomitant medications, including opioids 
● Electrocardiograms (ECGs) 
Cardiac function will be monitored via echocardiogram or multigated acquisition (MUGA) scans. The same 
modality (echocardiogram or MUGA scan) must be used throughout the study period. AEs will be collected 
from Cycle 1 Day 1 predose through 30 days after last dose of study drug. Study protocol-related SAEs will be 
collected from the time of signing the pre-screening or main informed consent for the study. Investigators 
should follow subjects with AEs until the event returns to baseline, stabilizes (recovering/resolving) or is no 
longer considered clinically significant by the investigator, or the subject dies, is lost to follow-up, or withdraws 
consent, or study closure.  
Safety and study conduct will be monitored throughout the study by an independent data monitoring committee 
(IDMC). The committee is tasked with monitoring the safety of participants in this study through regular and/or 
ad hoc meetings. An IDMC meeting will be held after the first 25 subjects enrolled have received at least 1 dose 
of zanidatamab. After the first IDMC meeting, subsequent meetings will be held quarterly to review cumulative 
safety data to identify any potential new safety signals. An additional IDMC meeting will be held at least 28 days 
after the tenth subject enrolled in China has received 1 dose of zanidatamab to review safety. The IDMC will be 
responsible for making recommendations to the sponsor as to appropriate study direction; further details will be 
provided in the IDMC charter. 
Quality of Life and Disease-Related Pain Assessments 
The EQ-5D-5L questionnaire will be used to obtain QOL information and the BPI short form will be used to 
assess disease-related pain at protocol-specified timepoints. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023  
ZWI-ZW25-203 
Amendment 3 
Page 9 of 97  
 
 
Confidential 
 
 
Statistical Methods 
This is a single-arm, open-label study that will enroll approximately 100 subjects: 75 subjects in Cohort 1, 
and 25 subjects in Cohort 2. The primary endpoint is the confirmed ORR by ICR. The primary efficacy 
analysis will evaluate this endpoint for the Cohort 1 Primary Efficacy Analysis Set, defined as all safety 
evaluable subjects in Cohort 1. The 2-sided Clopper-Pearson exact binomial 95% confidence intervals (CIs) 
that could be observed with a sample size of 75 subjects are listed in the table below. The primary analysis 
of efficacy will be performed approximately 6 months after the last subject has been enrolled in Cohort 1 of 
the study. 
 
Clopper-Pearson 95% Confidence Intervals for N = 75 Subjects 
Confirmed ORR 
95% CI 
Percent 
Responses 
Lower 
Upper 
20.0% 
15 
11.7% 
30.8% 
25.3% 
19 
16.0% 
36.7% 
30.7% 
23 
20.5% 
42.4% 
36.0% 
27 
25.2% 
47.9% 
40.0% 
30 
28.9% 
52.0% 
45.3% 
34 
33.8% 
57.3% 
50.7% 
38 
38.9% 
62.4% 
With a sample size of 100 subjects (Cohorts 1 and 2 combined), the binomial probabilities of detecting 1 or 
more treatment-emergent adverse events (TEAEs) with a frequency of 5%, 1%, and 0.1% are approximately 
0.99, 0.63, and 0.10, respectively. 
Summaries of subject disposition, demographics, disease characteristics, and exposure will be provided. Safety 
and efficacy endpoints will be summarized using descriptive statistics (e.g., mean, median, standard deviation, 
minimum, maximum) for continuous variables, and frequencies and percentages for categorical variables. In 
addition, the PK parameters of zanidatamab will be estimated and summarized with descriptive statistics. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 10 of 97 
 
Confidential 
 
Table 1: 
Schedule of Events 
Assessment 
Optional 
HER2 Pre-
Screening 
Screening  
(≤ 28 days) 
Evaluation Cycles 
(8 weeks) 
Subsequent 
28-Day Cycles 
Q8W Q12W EOTm 
Safety 
Follow-up 
(30 Days 
Post-Last 
Dose) 
Efficacy 
Follow-
up 
(Q8W) 
Survival 
Follow-up 
(Q3 mos)q 
Cycle 1 
Cycle 2 
D1 
D2 
D5 
D15 
(±2d) 
D1 
(±2d) 
D15 
(±2d) 
D28 
(±7d) 
D1 
(±2d) 
D15 
(±2d) 
(±7d) 
(±7d) 
(+7d) 
(+7d) 
 
(±7d) 
(±14d) 
Zanidatamab a 
X 
X 
X 
X 
X 
X 
Informed consent 
Xt 
X 
Medical history 
X 
Eligibility 
X 
X 
Demographics 
X 
New tumor biopsy or archived tissue 
Xg 
Xg 
Xk 
Disease assessment (CT/MRI)b 
X 
X 
Xb,w 
Xn 
X
o 
Xcc 
Brain scan bb 
X 
Xbb 
Xbb, cc 
Height 
X 
Weighth 
X 
X 
X 
X 
X 
X 
X 
Physical examc, h 
X 
X 
X 
X 
X 
X 
ECOG PSc, h 
X 
X 
X 
X 
X 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyc, h, v 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationd, h, v 
Xd 
Serum chemistryc, h, v 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisd, h 
Xd 
Pregnancy testc, h, r or question r 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Xd 
X 
Echo/MUGAh, l 
X 
First post-baseline scan at Cycle 3 Day 1 predose l, then every 12 weeks 
X 
Hepatitis B and C and HIVx 
X 
EQ-5D-5L and BPI questionnaires 
X 
X 
Xw 
X 
Assessment of opioid use 
X 
X 
Xw 
X 
ADAh, u 
X 
X 
X 
X 
Xj 
X 
X
p 
ctDNAh 
X 
X 
Xk 
HER2 ECDh 
X 
X 
X 
Xs 
Xk 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 11 of 97 
 
Confidential 
 
Assessment 
Optional 
HER2 Pre-
Screening 
Screening  
(≤ 28 days) 
Evaluation Cycles 
(8 weeks) 
Subsequent 
28-Day Cycles 
Q8W Q12W EOTm 
Safety 
Follow-up 
(30 Days 
Post-Last 
Dose) 
Efficacy 
Follow-
up 
(Q8W) 
Survival 
Follow-up 
(Q3 mos)q 
Cycle 1 
Cycle 2 
D1 
D2 
D5 
D15 
(±2d) 
D1 
(±2d) 
D15 
(±2d) 
D28 
(±7d) 
D1 
(±2d) 
D15 
(±2d) 
(±7d) 
(±7d) 
(+7d) 
(+7d) 
 
(±7d) 
(±14d) 
CA19-9 
 
X 
 
 
 
 
 
 
X 
 
 
Xw 
 
X 
 
Xcc 
 
PK samplese, f, u 
X 
Xi 
Xi 
X 
X 
X 
Xz,dd 
Xdd 
Xaa 
AEsy 
  
AEs and concomitant medications are recorded from Day 1 pre-dose through the end of the safety reporting 
period (30 days after the last dose of study treatment). Any study protocol-related SAE and concomitant 
medications given for treatment of the SAE, should be recorded from the time of signing the pre-screening or 
main informed consent for the study. 
Concomitant medications 
Subsequent anti-cancer therapies 
 
X 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 12 of 97 
 
Confidential 
 
Schedule of Events Footnotes 
Ab = antibody; ADA = anti-drug antibody; AE = adverse event; AESI = adverse event of special interest; Ag = antigen; BPI 
= brief pain inventory; CA19-9 = carbohydrate antigen 19-9; CR = complete response; CT = computed tomography; D or d = 
day; ECD = extracellular domain; ECG = electrocardiogram; Echo = echocardiogram; ECOG PS = Eastern Cooperative 
Oncology Group performance status; EOT = End of treatment; EQ-5D-5L = European Quality of Life 5-Dimensions 5-level 
questionnaire; HER2 = human epidermal growth factor receptor 2; HIV = human immunodeficiency virus; MRI = magnetic 
resonance imaging; MUGA = multigated acquisition scan; 
PK = pharmacokinetics; PR = partial response; PRO = patient-reported outcomes; Q3 mos = every 3 months; Q8W = every 8 
weeks; Q12W = every 12 weeks; SAE = serious adverse event 
a 
See Section 5 for zanidatamab dosing and administration. 
b 
After screening, all subsequent radiographic scans for disease assessments may be done within a ± 7-day window and 
based on 8-week intervals timed from Cycle 1 Day 1. Objective responses (CR or PR) must be confirmed 4 weeks (+7 days) 
following initial documentation of the response by the investigator. 
c 
Does not need to be repeated on Cycle 1 Day 1 if assessment completed for screening within the previous 3 days.  
d 
Repeated at subsequent cycles if medically indicated. 
e 
See Table 2 for extensive sampling timepoints, Table 3 for sparse sampling timepoints, and Table 4 for extensive 
sampling timepoints at steady state.  
f 
On applicable dosing days, the assessment should be performed pre-dose and post-dose. 
g 
See Section 7.1 for details. Only done at screening if not previously done as part of pre-screening.  
h    On applicable dosing days, the assessment should be performed pre-dose. 
i 
Not required for subjects on sparse PK sampling schedule.  
j 
Pre-dose on Day 1 of Cycles 4, 6, 8, 10, 12, 18, 24, and 36. 
k 
Only at disease progression. Tumor biopsy is optional and requires additional consent. 
l 
After screening, an echocardiogram/MUGA should be done predose within a -7-day window from Cycle 3 Day 1, then all 
subsequent scans should be done pre-dose every 3 cycles (Q12W) thereafter within a -7 day time window. An 
echocardiogram/MUGA is not required at EOT if 3 months since the previous scan. 
m Should take place as soon as possible after a subject permanently stops study treatment (within 7 days after treatment 
discontinuation). 
n 
Not required if  4 weeks since previous scan. 
o Only required if feasible, and last scan showed unconfirmed PR/CR and performed 4 weeks prior.  
p Not required if  2 weeks since last sample. 
q 
Every 3 months until death, lost to follow-up, withdrawal of consent, study completion, or study termination by the 
sponsor. 
r 
Urine pregnancy tests will be performed for women of childbearing potential on Day 1 of each cycle prior to dosing. A 
serum test must be performed if the urine pregnancy test is positive or equivocal. In the event that a urine pregnancy test is not 
available, a serum pregnancy test can be used instead. Male subjects with partners of childbearing potential will be asked to 
confirm their partner is not pregnant. 
s 
Pre-dose on Day 1 of Cycles 4, 8, and 12 only. 
t 
For subjects who opt to be prescreened for HER2 amplification status. 
u 
A blood sample for measurement of zanidatamab PK and ADA should be taken for any subject who experiences an AE 
that results in an unscheduled visit or meets SAE criteria, if less than 24 hours have elapsed since the last dose of 
zanidatamab. 
v 
Refer to Section 7.8.3 for specific parameters.  
w Timed from Cycle 1 Day 1. 
x 
HIV 1/2 Ag/Ab combination immunoassay. 
y 
All AEs should be followed until the event returns to baseline, stabilizes (recovering/resolving) or is no longer considered 
clinically significant by the investigator, or the subject dies, is lost to follow-up, withdraws consent, or study closure. 
z 
Day 1 of Cycles 4, 6, 8, 10, and 12 only. 
aa   Only required if subject has completed less than 6 months of treatment. 
bb  MRI or CT if MRI not feasible (CT with contrast unless medically contraindicated). For subjects with history or clinical 
suspicion of brain metastases, brain MRI or CT must be repeated at time of all tumor restaging. 
cc   Until disease progression or start of subsequent anticancer therapy. 
dd   For extensive PK sampling at steady state (Cycle 4 or later); see Table 4. 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 13 of 97 
 
 
Confidential 
 
 
 
Table 2: 
Pharmacokinetic Extensive Sampling Timepoints 
Time 
Cycle 1 
(4 Weeks) 
Cycle 2 
(4 Weeks) 
Additional Even- 
Numbered 
Cyclesa 
EOT 
D1 
D2 
D5 
D15 
D1 and D15 
D1 
Pre- 
dose 
End of 
ZW25 
Infusion 
2 h Post- 
dose 
4 h Post- 
dose 
8 h Post- 
dose 
24 h 
Post- 
dose 
96 h Post- 
dose 
 
Pre- 
dose 
End of 
ZW25 
Infusion 
Pre- dose 
End of 
ZW25 
Infusion 
Pre- dose 
End of 
ZW25 
Infusion 
Allowed 
time window 
 
+15 
min 
± 15 
min 
± 15 
min 
± 3 h 
±4 h 
± 4 h 
– 4 h 
+15 
min 
– 4 h 
+15 
min 
– 4 h 
+15 
min 
PK serum 
sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
D = day; EOT = end of treatment; h = hour; min = minute; PK = pharmacokinetics; ZW25 = zanidatamab  
Extensive sampling will be performed for the first 10 subjects enrolled in China and first 20 suitable subjects enrolled in the rest of world (suitability determined by medical 
monitor). 
a  Day 1 of Cycles 4, 6, 8, 10, and 12. 
b  Only required if subject has completed less than 6 months of treatment. 
 
Table 3: 
Pharmacokinetic Sparse Sampling Timepoints 
Time 
Cycle 1 
(4 Weeks) 
Cycle 2 
(4 Weeks) 
Additional Even-Numbered 
Cyclesa 
EOT 
D1 
D15 
D1 and D15 
D1 
Pre-dose 
End of ZW25 
Infusion 
Pre-dose 
End of ZW25 
Infusion 
Pre-dose 
End of ZW25 
Infusion 
Pre-dose 
End of ZW25 
Infusion 
Allowed time 
window 
 
+15 min 
– 4 h 
+15 min 
– 4 h 
+15 min 
– 4 h 
+15 min 
PK serum 
sample 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
D = day; EOT = end of treatment; h = hour; min = minute; PK = pharmacokinetics; ZW25 = zanidatamab  
a  Day 1 of Cycles 4, 6, 8, 10, and 12. 
b  Only required if subject has completed less than 6 months of treatment. 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 14 of 97 
 
 
Confidential 
 
 
 
Table 4: 
Steady-State Extensive Pharmacokinetic Sampling Schedule 
 
Cycle 4 or any Subsequent Cycle 
D1 
D3 
D5 
D15 
Time 
Pre-dosea 
End of 
ZW25 
infusion 
2 h  
post- 
dose 
4 h  
post- 
dose 
8 h 
 post-dose 
48 h post- 
dose 
96 h post- 
dose 
336 h post- 
dose 
Allowed time window 
 
+15 min 
± 15 min 
± 30 min 
± 3 hr 
± 1 day 
± 1 day 
± 3 days 
PK serum sample  
X 
X 
X 
X 
X 
X 
X 
X 
D=day; h=hour; min=minutes; PK=pharmacokinetic 
Extensive sampling at steady state will be performed for the first 10 suitable subjects in China who reach Cycle 4 and the first 20 suitable subjects in the rest of world who reach 
Cycle 4 (suitability determined by medical monitor). 
a  Relative to start of zanidatamab administration. 
Note: Dates and times of the start and end of zanidatamab infusions and dates and times of the PK samples must be recorded. 
Note: The sampling specified here is to be performed in addition to the sampling specified in  
Table 2 and Table 3. 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 15 of 97 
Confidential 
 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................2 
TABLE OF CONTENTS ...............................................................................................................15 
LIST OF IN-TEXT TABLES ........................................................................................................19 
LIST OF IN-TEXT FIGURES.......................................................................................................19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................20 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Biliary Tract Cancers ..................................................................................................24 
1.2. 
Standard of Care Therapies for Advanced or Metastatic BTC ...................................24 
1.3. 
HER2 Expression in BTC ...........................................................................................25 
1.4. 
Approved HER2-Targeted Therapies .........................................................................26 
1.5. 
HER2-targeted Therapies in BTC ...............................................................................26 
1.6. 
Zanidatamab ...............................................................................................................26 
1.7. 
Rationale for Zanidatamab in Recurrent/Relapsed BTC ............................................28 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................29 
3. 
INVESTIGATIONAL PLAN .....................................................................................30 
3.1. 
Summary of Study Design ..........................................................................................30 
3.2. 
Discussion and Rationale for Study Design ................................................................32 
3.2.1. 
Method of Assigning Subjects to Treatment Groups ..................................................33 
3.2.2. 
Rationale for Selection of Doses.................................................................................33 
3.2.3. 
Blinding ......................................................................................................................34 
4. 
STUDY POPULATION .............................................................................................34 
4.1. 
Inclusion Criteria ........................................................................................................34 
4.2. 
Exclusion Criteria .......................................................................................................35 
4.3. 
Childbearing Potential and Contraception ..................................................................36 
4.3.1. 
Definitions ..................................................................................................................36 
4.3.2. 
Methods of Contraception ..........................................................................................37 
4.4. 
Removal of Subjects From Therapy or Assessment ...................................................38 
4.4.1. 
Treatment Discontinuation .........................................................................................38 
4.4.2. 
Subject Withdrawal from Study .................................................................................39 
5. 
TREATMENTS ..........................................................................................................39 
5.1. 
Treatments Administered ............................................................................................39 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 16 of 97 
Confidential 
 
5.2. 
Investigational Study Drug (Zanidatamab) .................................................................39 
5.2.1. 
Description ..................................................................................................................40 
5.2.2. 
Dose and Administration ............................................................................................40 
5.2.3. 
Dose Modifications .....................................................................................................41 
5.2.4. 
Storage and Handling..................................................................................................45 
5.2.5. 
Packaging and Labeling ..............................................................................................45 
5.2.6. 
Preparation ..................................................................................................................45 
5.2.7. 
Concomitant Therapy .................................................................................................45 
5.3. 
Duration of Study Treatment ......................................................................................47 
5.4. 
Management of Infusion Reactions and Other Adverse Reactions ............................47 
5.5. 
Treatment Compliance ................................................................................................47 
6. 
STUDY ACTIVITIES ................................................................................................47 
6.1. 
Optional HER2 Pre-screening Visit (After Diagnosis and Prior to Screening 
Visit) ...........................................................................................................................47 
6.2. 
Screening Visit (Day –28 to 1) ...................................................................................48 
6.3. 
Treatment Period .........................................................................................................49 
6.3.1. 
Cycle 1 ........................................................................................................................49 
6.3.2. 
Cycle 2 ........................................................................................................................50 
6.3.3. 
Each Subsequent 28-Day Cycle ..................................................................................52 
6.3.4. 
Every 8 Weeks (±7 days); Timed from Cycle 1 Day 1 ..............................................53 
6.4. 
End of Treatment Visit ...............................................................................................53 
6.5. 
Safety Follow-up (Approximately 30 Days After the Last Dose of Study 
Drug) ...........................................................................................................................54 
6.6. 
Efficacy Follow-up (Every 8 Weeks) .........................................................................55 
6.7. 
Survival Follow-Up ....................................................................................................55 
7. 
STUDY ASSESSMENTS ..........................................................................................55 
7.1. 
Screening/Baseline Assessments ................................................................................55 
7.2. 
Response/Efficacy Assessments .................................................................................56 
7.3. 
Pharmacokinetic Assessments ....................................................................................56 
7.4. 
Biomarker Studies .......................................................................................................57 
7.5. 
Immunogenicity Assessments .....................................................................................58 
7.6. 
Biospecimen Repository .............................................................................................58 
7.7. 
Quality of Life and Disease-Related Pain Assessments .............................................58 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 17 of 97 
Confidential 
 
7.8. 
Safety Assessments .....................................................................................................59 
7.8.1. 
Adverse Events ...........................................................................................................59 
7.8.2. 
Adverse Events of Special Interest .............................................................................64 
7.8.3. 
Clinical Laboratory Tests ............................................................................................64 
7.8.4. 
Vital Signs ..................................................................................................................65 
7.8.5. 
Physical Examination .................................................................................................65 
7.8.6. 
ECOG Performance Status .........................................................................................65 
7.8.7. 
Electrocardiogram .......................................................................................................65 
7.8.8. 
Echocardiogram/MUGA .............................................................................................66 
7.9. 
Appropriateness of Measurements ..............................................................................66 
8. 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ..............................66 
8.1. 
Audit and Inspection ...................................................................................................66 
8.2. 
Monitoring ..................................................................................................................66 
8.3. 
Data Management and Coding ...................................................................................67 
8.4. 
Drug Accountability ...................................................................................................67 
9. 
DATA ANALYSIS METHODS ................................................................................67 
9.1. 
Statistical Hypotheses .................................................................................................67 
9.2. 
Determination of Sample Size ....................................................................................68 
9.3. 
Analysis Sets ...............................................................................................................69 
9.4. 
Statistical and Analytical Plans ...................................................................................70 
9.4.1. 
General Considerations ...............................................................................................70 
9.4.2. 
Subject Disposition .....................................................................................................71 
9.4.3. 
Subject Characteristics ................................................................................................71 
9.4.4. 
Treatment Compliance ................................................................................................71 
9.4.5. 
Concomitant Medications ...........................................................................................71 
9.4.6. 
Efficacy Analyses .......................................................................................................71 
9.4.7. 
Pharmacokinetic Analyses ..........................................................................................73 
9.4.8. 
Immunogenicity Analyses ..........................................................................................73 
9.4.9. 
Biomarker Analyses ....................................................................................................74 
9.4.10. 
Safety Analyses ...........................................................................................................74 
9.4.11. 
Timing of Analyses .....................................................................................................75 
9.4.12. 
Independent Data Monitoring Committee ..................................................................75 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 18 of 97 
Confidential 
 
10. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS ..................................................................................................76 
10.1. 
Institutional Review Board/Independent Ethics Committee .......................................76 
10.2. 
Regulatory Authorities ................................................................................................76 
10.3. 
Ethical Conduct of the Study ......................................................................................76 
10.4. 
Informed Consent .......................................................................................................76 
10.4.1. 
Subject Confidentiality ...............................................................................................77 
10.5. 
Study Documentation and Records Retention ............................................................77 
10.6. 
Clinical Trial Agreement ............................................................................................78 
11. 
REFERENCES ...........................................................................................................79 
APPENDIX A. ECOG PERFORMANCE STATUS SCALE ....................................................81 
APPENDIX B. INVESTIGATOR SIGNATURE PAGE ...........................................................82 
APPENDIX C. QTCF EQUATION............................................................................................83 
APPENDIX D. DOCUMENT HISTORY ..................................................................................84 
PROTOCOL APPROVAL SIGNATURE .....................................................................................97 
 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 19 of 97 
Confidential 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Schedule of Events......................................................................................................10 
Table 2: 
Pharmacokinetic Extensive Sampling Timepoints .....................................................13 
Table 3: 
Pharmacokinetic Sparse Sampling Timepoints ..........................................................13 
Table 4: 
Steady-State Extensive Pharmacokinetic Sampling Schedule ...................................14 
Table 5: 
Acceptable Methods of Highly Effective Birth Control .............................................38 
Table 6: 
Unacceptable Methods of Birth Control .....................................................................38 
Table 7: 
Recommended Management and Potential Dose Modifications for 
Zanidatamab-Associated Toxicity ..............................................................................41 
Table 8: 
Management of Left Ventricular Dysfunction ............................................................43 
Table 9: 
Zanidatamab Treatment Modification for Symptoms of Infusion-Related 
Reactions .....................................................................................................................44 
Table 10: Clopper-Pearson 95% Confidence Intervals for N = 75 Subjects ...............................69 
Table 11: Clopper-Pearson 95% Confidence Intervals for N=25 Subjects .................................69 
Table 12: Probabilities of Detecting ≥ 1 Adverse Event .............................................................69 
Table 13: Subject Analysis Sets ..................................................................................................70 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Study Design ...............................................................................................................32 
Figure 2: 
Structure of Zanidatamab ...........................................................................................40 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 20 of 97 
Confidential 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
λz 
terminal elimination rate constant 
5-FU 
5-fluorouracil 
5-HT3 
5-hydroxytryptamine 
ADA 
anti-drug antibody 
ADC 
antibody-drug conjugate 
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse event 
AESI 
adverse event of special interest 
AJCC 
American Joint Committee on Cancer 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASC 
active symptom control 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the serum concentration-time curve from zero to infinity 
AUC0-t 
area under the serum concentration-time curve from zero to the last measurable 
concentration 
AUCtau 
area under the serum concentration-time curve from zero to the end of dosing interval 
ß-hCG 
beta-human chorionic gonadotropin 
BOR 
best overall response 
BPI 
Brief Pain Inventory 
BTC 
biliary tract cancer 
BUN 
blood urea nitrogen 
Cave 
average concentration 
CA19-9 
carbohydrate antigen 19-9 
CC 
cholangiocarcinoma 
CD4 
cluster of differentiation 4 
CDx 
companion diagnostics 
CFR 
Code of Federal Regulations 
CH 
constant heavy chain 
CHF 
congestive heart failure 
CisGem 
cisplatin and gemcitabine 
CI 
confidence interval 
CL 
serum clearance 
CLIA 
Clinical Laboratory Improvements Amendment 
Cmax 
maximum concentration 
Cmin 
minimum concentration 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CSS 
steady state concentration 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 21 of 97 
Confidential 
 
CTFG 
Clinical Trial Facilitation Group 
DCR 
disease control rate 
DOR 
duration of response 
DLT 
dose-limiting toxicity 
ECC 
extrahepatic cholangiocarcinoma 
ECD 
extracellular domain 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR/ErbB 
epidermal growth factor receptor 
EOT 
end of treatment 
EQ-5D-5L 
European Quality of Life 5-Dimensions 5-level questionnaire 
ESMO 
European Society for Medical Oncology 
Fab 
fragment antigen-binding 
Fc 
fragment crystallizable 
EU 
European Union 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FGFR2 
fibroblast growth factor receptor 2 
FISH 
fluorescence in situ hybridization 
FNAs 
fine needle aspirates 
FSH 
follicle stimulating hormone 
GBC 
gallbladder cancer 
GCP 
Good Clinical Practice 
GEA 
gastroesophageal adenocarcinoma 
GFR 
glomerular filtration rate 
H2 
histamine-2 receptor antagonist 
HER2 
human epidermal growth factor receptor 2 
Hgb 
hemoglobin 
hIgG 
human immunoglobulin 
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell carcinoma 
HR 
hazard ratio 
ICC 
intrahepatic cholangiocarcinoma 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICR 
independent central review 
IDH 
isocitrate dehydrogenase 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IgG 
immunoglobulin G 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
institutional review board 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
IUO 
investigational use only 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 22 of 97 
Confidential 
 
IV 
intravenous(ly) 
LMD 
leptomeningeal disease 
LVEF 
left ventricular ejection fraction 
MAPK 
mitogen-activated protein kinase 
MCH 
mean corpuscular hemoglobin 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFOLFOX 
modified FOLFOX (folinic acid [leucovorin], 5-FU, and oxaliplatin) 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MUGA 
multigated acquisition scan 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NGS 
next generation sequencing 
NK-1 
neurokinin-1 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PI3K 
phosphoinositide 3-kinase 
PK 
pharmacokinetic(s) 
PO 
per oral (orally) 
PR 
partial response 
PRO 
patient-reported outcome 
PS 
performance status 
PT 
prothrombin time 
QxH 
every x hours 
Qx mos 
every x months 
QxW 
every x weeks 
QOL 
quality of life 
QTcF 
QTc Fridericia 
RBC 
red blood cell 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RD 
recommended dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
scFv 
single-chain variable fragment 
Scr 
serum creatinine 
SD 
stable disease 
SOC 
system organ class 
T-DM1 
ado-trastuzumab emtansine 
TEAE 
treatment-emergent adverse event 
t1/2 
half-life 
tmax 
time to maximum concentration 
ULN 
upper limit of normal 
US 
United States 
Vd 
volume of distribution 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 23 of 97 
Confidential 
 
VH 
variable heavy 
VL 
variable light 
WBC 
white blood cell 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 


Jazz Pharmaceuticals Ireland, Limited 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 24 of 97 
Confidential 
1.
INTRODUCTION
1.1. 
Biliary Tract Cancers 
Biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CC) 
(both intrahepatic cholangiocarcinoma [ICC] and extrahepatic cholangiocarcinoma [ECC]), are 
poor prognosis cancers that account for approximately 3% of all adult cancers (Valle 2017). 
BTCs represent a heterogeneous group of diseases that are associated with distinct risk factors, 
molecular characteristics, and symptoms at presentation. For example, the liver fluke Opistorchis 
viverrini infection is a risk factor for ICC and ECC but not GBC, while patients with GBC are 
less likely to present with jaundice compared to patients with ICC or ECC (Valle 2017). 
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) and fibroblast growth factor receptor 2 
(FGFR2) are more prevalent in patients with ICC (Valle 2017); (Arai 2014). Recent studies with 
small molecule inhibitors of IDH1 or FGFR2 have demonstrated clinical activity in patients with 
advanced CC containing these respective gene mutations (A. Vogel 2019, Abou-Alfa 2019). 
Human epidermal growth factor receptor 2 (HER2) amplification, which is more frequent in 
GBC, represents another potential molecular treatment target (Valle 2017). 
The incidence and mortality rates of BTCs are increasing, mostly due to a rise in the incidence of 
ICC. More than 65% of patients with BTC are diagnosed with non-resectable disease and the 
relapse rate is high among patients who undergo potentially curative surgery. The 5-year survival 
rate is approximately 5 to 15% for all patients; the estimated 5-year survival rate varies by stage 
of disease: 50% for American Joint Committee on Cancer (AJCC) Stage I, 30% for Stage II, 
10% for Stage III, and 0% for Stage IV (Valle 2017). 
1.2. 
Standard of Care Therapies for Advanced or Metastatic BTC 
The most active cytotoxic chemotherapeutics for advanced BTCs are gemcitabine- and platinum-
containing regimens (Tsavaris 2004, Eckel 2007). In a randomized, multicenter, 
Phase 3 trial of 410 subjects (the ABC-02 Study), cisplatin combined with gemcitabine 
(CisGem) was associated with superior overall survival (OS) and progression-free survival (PFS) 
compared to gemcitabine alone in the first-line setting of advanced or metastatic BTC (Valle 
2010). These results were replicated in a randomized Phase 2 trial conducted in Japan (the BT22 
Study) (Okusaka 2010). Based on these results, CisGem has become the recognized standard 
regimen for first-line treatment of patients with advanced BTC. In the second-line setting, the 
most robust data comes from a recent Phase 3 trial (the ABC-06 Study), in which 162 subjects 
were randomized 1:1 to receive either mFOLFOX (folinic acid [leucovorin], 5-fluorouracil [5- 
FU], and oxaliplatin) plus active symptom control (ASC), versus ASC alone. The median OS for 
subjects treated with mFOLFOX plus ASC was 6.2 months versus 5.3 months for subjects who 
received ASC alone (hazard ratio [HR] 0.69, 95% CI: 0.50, 0.97, p = 0.031). The PFS and 
objective response rate (ORR) with mFOLFOX + ASC was 4 months and 5%, respectively; the 
PFS and ORR with ASC alone was not reported (Lamarca 2019). Other than the ABC-06 trial, 
there are no other published randomized data in the second-line and later BTC setting. 
Given the lack of second-line systemic treatments showing clinically meaningful benefit for 
patients with advanced BTC, there remains a need for new treatment approaches, including 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 25 of 97 
Confidential 
 
molecularly targeted therapies. Several targeted agents have entered clinical development with 
encouraging results, including HER2-directed therapies. Pemigatinib (PEMAZYRE™), a small 
molecule kinase inhibitor, was recently approved for the treatment of patients with previously 
treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or 
other rearrangement.  
1.3. 
HER2 Expression in BTC 
HER2 is a member of the epidermal growth factor receptor (EGFR/ErbB) family comprising 
4 structurally related receptors: HER1 (EGFR), HER2, HER3, and HER4. HER receptors are 
normally activated by binding to specific ligands, resulting in a conformational change that 
allows formation of receptor homodimers and heterodimers. Receptor dimerization triggers 
autophosphorylation of specific tyrosine residues and activation of intracellular signaling 
pathways. Over-expression and amplification drive tumorigenesis through the creation of 
spontaneous receptor homodimers or heterodimers with other ErbB family members, resulting in 
activated oncogenic downstream signaling such as phosphoinositide 3-kinase 
(PI3K)/AKT/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase 
(MAPK), which in turn promote cellular proliferation, survival and angiogenesis (Moasser 
2007). HER2 is a well-described predictive biomarker for anti-HER2 therapy in breast and 
gastric cancer (Slamon 2001, Bang 2010) and many other solid tumors also harbor HER2 gene 
amplification or over-expression (Meric-Bernstam 2019). However, data from published series 
of HER2 expression across solid tumors vary both in terms of methodology and reporting, and 
their utility is consequently limited. 
A systematic literature review and meta-analysis of published data in BTC showed that among 
38 studies (a total of 3839 patients) that reported HER2 positivity assessed by 
immunohistochemistry (IHC), the mean prevalence of HER2 overexpression was 26.5% (95% 
CI: 18.9, 34.1%) (Galdy 2017). There was no statistically significant difference in HER2 
overexpression between regions; the mean prevalence of HER2 overexpression in Asia was 
28.4% (95% CI: 14.5, 42.3%) versus 19.7% (95% CI: 10.1, 29.2%) for Western countries, 
P value = 0.49. When all 38 studies were considered, no differences in the mean prevalence of 
HER2 overexpression were found between BTC tumor subtypes. However, when only studies 
that defined HER2 overexpression as the presence of moderate/strong staining were considered, 
the mean prevalence of HER2 overexpression was highest for GBC (19.1%), followed by ECC 
(17.4%), and ICC (4.8%). HER2 amplification analysis was performed in 16 of the 38 studies 
and showed a mean prevalence of 30.1%. The mean prevalence of HER2 amplification for ECC 
was 22.5% and 17.6 % for ICC; the prevalence was not reported for GBC (not all of the 16 
studies reported the prevalence of HER2 amplification by BTC subtype). A separate study of 
221 patients with BTC showed good correlation between HER2 overexpression and gene 
amplification (78% concordance rate) (Nakazawa 2005). 
Similar to breast and gastric cancers, a number of studies have suggested that HER2 
overexpression or gene amplification has biologic importance or clinical relevance in BTCs. 
Constitutive expression of HER2 in gallbladder epithelium led to the development of 
adenocarcinoma in transgenic mice (Kiguchi 2001) and high HER2 expression in a 
cholangiocarcinoma cell line resulted in enhanced invasiveness, motility, and proliferation via 
AKT/p70S6K pathway activation, compared with cell lines without HER2 overexpression 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 26 of 97 
Confidential 
 
(Treekitkarnmongkol 2010). Furthermore, in a HER2-amplified GBC cell line, SNU-2670, 
trastuzumab demonstrated anti-tumor effects as monotherapy and in combination with 
gemcitabine, promoting increased apoptosis compared to cell lines without HER2 amplification 
(Nam 2016). 
1.4. 
Approved HER2-Targeted Therapies 
The introduction of HER2-targeted therapy into the clinic has led to marked improvements in 
disease-free survival, PFS, and OS for patients with HER2-high breast cancer (Schramm 2015). 
In the United States (US), there are multiple approved HER2-targeted agents, all of which are 
indicated for the treatment of HER2-high breast cancer. These include the antibody-based 
therapies trastuzumab (HERCEPTIN® and biosimilars), pertuzumab (PERJETA®), and 
margetuximab (MARGENZA™), the antibody-drug conjugates (ADCs) ado-trastuzumab 
emantasine (KADCYLA®; also referred to as T-DM1) and fam-trastuzumab deruxtecan-nxki 
(ENHERTU®; also referred to as DS-8201a); the oral small molecule dual EGFR/HER2 inhibitor 
lapatinib (TYKERB®); the irreversible oral small molecule EGFR/HER2/HER4 inhibitor 
neratinib (NERLYNX®); and the tyrosine kinase inhibitor tucatinib (TUKYSA™). Trastuzumab 
is also approved for advanced HER2-overexpressing gastric/gastroesophageal junction cancer. 
There are no approved HER2 agents for any other HER2-high expressing cancers, or for cancers 
with lower levels of HER2 expression and absence of gene amplification. 
1.5. 
HER2-targeted Therapies in BTC 
Of the HER2-targeted agents, lapatinib has been evaluated in both the first- and second-line 
setting in an unselected population of subjects with advanced BTC (Ramanathan 2009, 
Peck 2012). Results of these studies were unremarkable and showed no significant evidence of 
anti-tumor activity. However, in a separate case series of 9 GBC and 5 CC subjects treated with 
trastuzumab, lapatinib, or pertuzumab monotherapy, 4/9 GBC subjects (44.4%) had partial 
responses (PR) and 1/9 GBC subject (11.1%) had a complete response (CR), equating to an ORR 
of 55.6% (Javle 2015). An additional 3 GBC subjects had stable disease (SD). The duration of 
response (DOR) ranged from 8+ to 168 weeks (median 40 weeks). All 5 GBC subjects with 
objective responses had HER2 overexpression or amplification. The clinical benefit of 
HER2-targeted agents may therefore be associated with HER2 amplification or over-expression, 
and a biomarker-based strategy is needed to select patients for HER2-directed therapies. 
1.6. 
Zanidatamab 
Zanidatamab (formerly referred to as ZW25) is a novel humanized, bispecific antibody that binds 
to the same 2 extracellular domains of HER2 as trastuzumab (ECD4) and pertuzumab (ECD2). 
Binding of zanidatamab results in blockade of ligand-dependent and independent growth and 
potent activation of antibody-dependent cellular cytotoxicity (ADCC). The unique binding 
geometry of zanidatamab also leads to increased tumor cell binding, receptor clustering, and 
receptor internalization relative to trastuzumab, including in settings of lower HER2 expression. 
A brief summary of zanidatamab nonclinical and clinical data is provided below; additional data 
are presented in the Investigator’s Brochure. Planned and ongoing clinical studies are also 
summarized in the Investigator’s Brochure. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 27 of 97 
Confidential 
 
In preclinical studies in tumor cell lines and xenograft tumor models, zanidatamab demonstrated 
anti-tumor activity that was superior to trastuzumab across a range of tumors and HER2 
expression levels. Zanidatamab treatment of mice bearing HER2 1+ patient-derived breast cancer 
xenografts (ST1337B) significantly improved host survival compared with trastuzumab or 
human immunoglobulin (hIgG). Zanidatamab was also efficacious in nude mice bearing 
established tumors with a human non-small cell lung cancer (NSCLC) or head and neck 
squamous cell carcinoma (HNSCC) cell lines (A549 and FaDu cell lines, both HER2 < 3+, 
respectively). In addition, zanidatamab was efficacious in nude mice bearing established tumors 
with the human SKOV- 3 ovarian epithelial adenocarcinoma cell line that has a 3+ level of 
HER2 expression. 
An ongoing first-in-human study of zanidatamab, a multi-part Phase 1 trial (ZWI-ZW25-101; 
NCT02892123), is evaluating the safety, pharmacokinetics (PK), immunogenicity, and potential 
anti-tumor activity of zanidatamab as a single agent and in combination with selected 
chemotherapy agents in subjects with locally advanced (unresectable) and/or metastatic 
HER2-expressing tumors. Part 1 of the study used a standard 3+3 dose-escalation design to 
determine the maximum-tolerated dose (MTD), optimal biological dose, or recommended dosage 
(RD) of zanidatamab monotherapy administered every week (QW), once every 2 weeks (Q2W), 
or once every 3 weeks (Q3W) to subjects with any HER2-expressing cancer that had progressed 
after receipt of all therapies known to confer clinical benefit. The QW or Q2W dosing cohorts 
completed enrollment with no dose-limiting toxicities (DLTs) and the MTD was not reached. 
The single agent RD for further study was identified as 10 mg/kg QW or 20 mg/kg Q2W. Part 2 
of Study ZWI-ZW25-101 is evaluating the safety, tolerability, and preliminary anti-tumor 
activity of zanidatamab monotherapy administered at a Part 1 RD in subjects with selected 
HER2-expressing locally advanced and/or metastatic cancers in up to 5 disease-specific cohorts, 
including HER2-high breast cancer (IHC 3+, or IHC 2+/ fluorescence in situ hybridization 
[FISH+]), HER2-intermediate breast cancer (IHC 2+/FISH-negative [FISH-]), HER2-high 
gastroesophageal adenocarcinoma (GEA), HER2-intermediate GEA, and other HER2-high solid 
tumors. Subjects eligible for Part 2 must have central confirmation of HER2 status based on new 
biopsies or archival tissues obtained ≤6 months without intervening HER2-directed agents. 
Part 3 of the study is evaluating the safety, tolerability, and preliminary anti-tumor activity of 
zanidatamab administered in combination with selected chemotherapy agents, including 
paclitaxel, capecitabine, and vinorelbine, in subjects with HER2-expressing breast and gastric 
cancers. 
Safety and anti-tumor activity data of zanidatamab monotherapy in GEA and other solid tumors 
was presented at the European Society for Medical Oncology (ESMO) 2019 annual meeting 
(Meric-Bernstam 2019). Among the 58 subjects enrolled in Part 1 and 2, the median age was 
61 years (range 26–81); 60% were male and 86% had an Eastern Cooperative Oncology Group 
(ECOG) performance status (PS) of 1. The median number of prior cancer regimens was 
4 (range 1–10), and 55% had received prior HER2 therapy. A total of 20/23 GEA subjects (87%) 
had received prior trastuzumab and 1 subject each (4%) had received T-DM1 and neratinib. Only 
2/9 BTC subjects (22%) had received prior trastuzumab; none of the remaining BTC subjects 
had received prior HER2-targeted agents. 
All treatment-related adverse events (AEs) were Grade 1 or 2. The most common treatment- 
related AEs were diarrhea (26 subjects, 45%) and infusion reaction (16 subjects, 28%). There 
were no treatment-related left ventricular ejection fraction (LVEF) decreases ≥ 10% during 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 28 of 97 
Confidential 
 
treatment. A single subject had a treatment-related serious adverse event (SAE), which was 
Grade 2 fatigue. Analyses of 10 mg/kg QW and 20 mg/kg Q2W dosing showed dose-
proportional and non-linear PK, with steady state reached by the end of Cycle 2. The half-life 
(t1/2) of 10 mg/kg QW was approximately 123 hours, and the t1/2 of 20 mg/kg Q2W was 
approximately 150 hours. The overall exposure was similar for 10 mg/kg QW and 20 mg/kg 
Q2W. The trough values were maintained above the minimum predicted efficacious level. 
Among all 46 response-evaluable subjects, the ORR (all PRs) was 35% (16/46 subjects). The 
disease control rate (DCR) was 72% (33/46). The median time on treatment for responding 
subjects was 5.1 months (range, 3.3 to 14.2). With the exception of 2 subjects, all responding 
subjects had HER2 amplification confirmed by central review. 
The ORR for response-evaluable subjects with BTC was 67% (4/6 subjects); all responses were 
confirmed. Among the 4 BTC subjects with confirmed objective responses, 3 had GBC and 
1 had ICC. Three of the 4 responding subjects with BTC had HER2 amplification confirmed by 
central review. 
Based on the above safety and efficacy results, zanidatamab monotherapy was generally well 
tolerated and has shown promising clinical activity across a range of advanced solid tumors; in 
particular, the ORR was high in subjects with BTCs with HER2 overexpression and 
amplification. 
1.7. 
Rationale for Zanidatamab in Recurrent/Relapsed BTC 
Due to the lack of treatment options for patients with recurrent/relapsed BTC after frontline 
CisGem, targeted therapies are attractive options for patients with specific genomic alterations. 
To date, studies have shown that HER2 is a relevant target in BTC. Similar to breast cancer or 
GEA, there is evidence to suggest that HER2 genomic alterations may drive or promote 
oncogenesis, and HER2-targeted agents have clinical activity in tumors that harbor HER2 over-
expression or amplification. In the ZWI-ZW25-101 Phase 1 trial, zanidatamab monotherapy is 
associated with promising clinical benefit in heavily pre-treated BTC subjects. The current 
Phase 2b trial is therefore designed to confirm the anti-tumor activity of zanidatamab in subjects 
with relapsed/refractory, HER2-amplified BTC in the second-line and later setting. 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 29 of 97 
Confidential 
 
2. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary: 
• To evaluate the anti-tumor activity of zanidatamab 
monotherapy in subjects with advanced or metastatic 
HER2-amplified biliary tract cancers (BTC) 
 
• Confirmed objective response rate (ORR) by 
the Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1), assessed by 
independent central review (ICR) 
Secondary: 
• To further evaluate the anti-tumor activity of 
zanidatamab monotherapy in subjects with 
advanced or metastatic HER2-amplified BTC 
 
• Duration of response (DOR) by RECIST 1.1 
assessed by ICR 
• Proportion of subjects with a DOR ≥16 weeks 
by RECIST 1.1 assessed by ICR 
• Disease control rate (DCR) by RECIST 1.1 
assessed by ICR 
• Progression-free survival (PFS) by RECIST 
1.1 assessed by ICR 
• ORR by RECIST 1.1 assessed by investigator 
• DOR by RECIST 1.1 assessed by investigator 
• Proportion of subjects with a DOR ≥16 weeks 
by RECIST 1.1 assessed by investigator 
• DCR by RECIST 1.1 assessed by investigator 
• PFS by RECIST 1.1 assessed by investigator 
• Overall survival (OS) 
 
• To evaluate the safety and tolerability of zanidatamab 
monotherapy in subjects with advanced or metastatic 
HER2-amplified BTC 
• Frequency and severity of adverse events 
(AEs) 
• Frequency of serious adverse events (SAEs) 
and deaths 
• Frequency and severity of clinical laboratory 
abnormalities 
• Frequency of dose modifications of 
zanidatamab 
 
• To evaluate the pharmacokinetics (PK) of 
zanidatamab 
• Serum concentrations of zanidatamab as a 
function of time post-dosing 
• PK parameters for single (first) dose and 
multiple doses 
 
• To evaluate the immunogenicity of zanidatamab 
• Frequency, duration, and time of onset of anti-
drug antibodies (ADA) and neutralizing 
antibodies, if applicable 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 30 of 97 
Confidential 
 
Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This pivotal, multicenter, open-label, single-arm trial will evaluate the anti-tumor activity of 
zanidatamab monotherapy in subjects with HER2-amplified, inoperable and advanced or 
metastatic BTC, including ICC, ECC, and GBC. Subjects must have received at least 1 prior 
gemcitabine-containing systemic chemotherapy regimen for advanced disease, and have 
experienced disease progression after or developed intolerance to the most recent prior therapy. 
New or archival tumor tissue is required from all subjects for HER2 amplification and HER2 
protein expression testing at a central lab using in situ hybridization (ISH) and 
immunohistochemistry (IHC) assays. Subjects may be tested for HER2 status at the central lab 
any time after diagnosis of advanced or metastatic disease and before study enrollment. Subjects 
who elect to be pre-screened for HER2 status must sign a separate informed consent for 
collection, storage, and analysis of the tumor tissue. Once a prospective subject experiences 
disease progression or develops intolerance to their most recent prior therapy, the main consent 
for the remaining screening assessments must be signed. 
Two cohorts of subjects will be enrolled: 
• Cohort 1, comprising approximately 75 subjects with HER2 amplification by ISH and 
HER2 overexpression by IHC; i.e., IHC 2+ or 3+ 
• Cohort 2, comprising approximately 25 subjects with HER2 amplification by ISH and 
HER2 IHC 0 or 1+ 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 31 of 97 
Confidential 
 
Enrolled subjects will receive zanidatamab, 20 mg/kg given intravenously (IV) Q2W until 1 of 
the treatment discontinuation criteria is met (see Section 4.4.1). Unequivocal clinical progression 
is defined as worsening or re-emergence of pre-existing symptoms relating to underlying cancers 
(e.g., increase in disease-related pain), or emergence of new symptoms that cannot be attributed 
to study drug toxicities or alternative causes. A marked deterioration in ECOG PS may also 
indicate unequivocal clinical progression. Subjects who discontinue treatment with zanidatamab 
for reasons other than progressive disease or start of subsequent anticancer therapy will continue 
in follow-up with disease assessments approximately every 8 weeks after the previous scan until 
disease progression or start of subsequent anticancer therapy. Responses that are initially 
observed during this follow-up period should be confirmed with disease assessment 4 weeks 
later. Following progression or start of subsequent anticancer therapy, disease assessments will 
be discontinued, and subjects will enter long-term follow-up for survival status. Data on survival 
will be collected via clinic visits (if feasible) or via telephone calls every 3 months after the last 
follow-up visit. Subjects may be discontinued from the study due to death, lost to follow-up, 
consent withdrawal, or study termination by sponsor. 
Computed tomography (CT) and/or magnetic resonance imaging (MRI) scans will be performed 
at baseline and every 8 weeks (Q8W) during treatment timed from Cycle 1 Day 1 and will 
continue after treatment discontinuation every 8 weeks until disease progression or start of 
subsequent anticancer therapy. Disease response will be assessed according to RECIST 1.1 by 
ICR (primary endpoint) and investigator (secondary endpoint); responses are to be confirmed 
4 weeks following initial documentation of objective response by the investigator. 
Safety will be monitored by recording the type, frequency, and severity of AEs graded using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 5.0 (27 November 2017). Safety assessments will include monitoring for SAEs, adverse 
events of special interest (AESIs; infusion-related reactions [IRRs], non-infectious pulmonary 
toxicities, and cardiac events of absolute decrease in LVEF of ≥ 10 percentage points from 
pretreatment baseline and absolute value < 50%, and/or grade ≥ 2 heart failure), deaths, clinical 
laboratory values, physical examinations, cardiac function, vital signs, body weight, and ECOG 
PS. Safety and study conduct will be monitored by an independent data monitoring committee 
(IDMC), which will be tasked with monitoring the safety of participants through regular and/or 
ad hoc meetings (see Section 9.4.12). 
Blood samples will be collected at protocol-specified timepoints for evaluation of zanidatamab 
PK and ADA. 
 
 
 
 
Tumor biopsies will be collected from all subjects at either pre-screening or screening and 
processed as formalin-fixed, paraffin-embedded (FFPE) tissues to assess HER2 amplification, 
protein expression, and exploratory biomarkers of response. Archival tumor tissue may also be 
used. If possible, an additional optional tumor biopsy is to be obtained at the time of disease 
progression from an accessible site to allow for assessment of changes in HER2 expression as 
well as the presence of other exploratory biomarkers. Biomarkers of response may be evaluated. 
Only the biomarkers specified above will be tested on samples collected in Mainland China. 
A study schema is presented in Figure 1. The schedule of assessments is presented in Table 1. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 32 of 97 
Confidential 
 
Figure 1: 
Study Design 
CT = computed tomography; EOT = end of treatment; IV = intravenous; MRI = magnetic resonance imaging; 
ZW25 = zanidatamab 
* Timed from Cycle 1 Day 1. 
** Subjects may be tested for HER2 status any time after diagnosis of advanced or metastatic disease and 
before study enrollment. Subjects who elect to be pre-screened for HER2 status must sign a separate informed 
consent for collection, storage, and analysis of the tumor tissue. 
*** Every 8 weeks until disease progression or start of subsequent anticancer therapy. 
**** Every 3 months until death, lost to follow-up, withdrawal of consent, study completion, or study 
termination by sponsor. 
 
3.2. 
Discussion and Rationale for Study Design 
The prognosis for patients with advanced BTC is very poor, with an estimated 5-year survival 
rate of approximately 5 to 15% for all patients (Valle 2017). Gemcitabine combined with a 
platinum agent has become the recognized standard regimen for first-line treatment of patients 
with advanced BTC (Okusaka 2010, Valle 2010). In the second-line setting, results of a recent 
Phase 3 trial (the ABC-06 Study) showed a median OS benefit of 0.9 months for subjects treated 
with mFOLFOX plus ASC compared with those who received ASC alone (HR 0.69, 95% CI: 
0.50, 0.97, p = 0.031). However, mFOLFOX treatment was associated with a higher rate of 
Grade 3/4 AEs (59% vs. 39%) and 3 of 81 treated subjects died from chemotherapy-related 
toxicities (Lamarca 2019). Other than the ABC-06 trial, there are no other published randomized 
data in the second-line and later BTC setting. Pemigatinib was granted approval for the treatment 
of patients with previously treated, unresectable locally advanced or metastatic 
cholangiocarcinoma based on ORR and DOR. In the FIGHT-202 trial, 107 subjects were treated in 
the open-label, single-arm study. The ORR was 36% (95% confidence interval [CI]: 27, 45), with a 
median DOR of 9.1 months (95% CI: 6.0, 14.5) (PEMAZYRE™). 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 33 of 97 
Confidential 
 
Studies have shown that HER2 is over-expressed in BTC, and HER2-targeted agents 
demonstrate clinical activity in tumors that harbor HER2 over-expression or amplification 
(Kiguchi 2001, Nakazawa 2005, Treekitkarnmongkol 2010, Galdy 2017) and (Nam 2016). 
However, no HER2-targeted agents are approved for treatment of patients with BTC. Given the 
high unmet medical need for this patient population and the promising anti-tumor activity and 
tolerability of zanidatamab monotherapy in BTC, a single-arm study design is considered 
appropriate. 
Data from studies in other pathologies indicate that antibody targeting of HER2 is most effective 
in disease that is HER2 amplified and shows intermediate-to-high levels of protein expression by 
IHC. In the ToGA study 22.4% of enrolled subjects had FISH positive/IHC 0 or FISH 
positive/IHC 1+ disease (Bang 2010). A post-hoc exploratory survival analysis failed to show a 
trend for benefit from the addition of trastuzumab to frontline chemotherapy (Bang 2010). The 
recently reported results of the colorectal cohort of the MyPathway study that treated 57 subjects 
with HER2 amplified disease demonstrated an overall ORR of 32% (18/57 subjects). However, 
no objective responses were observed in the 8 subjects who did not have high levels of protein 
expression by IHC (Meric-Bernstam 2019). The primary efficacy population for the current 
study will therefore comprise subjects with disease that is HER2 amplified by ISH and IHC 2+ 
or 3+ (Cohort 1, N = 75; see Section 3.1). To evaluate the activity of zanidatamab in subjects 
with lower levels of HER2 expression, subjects with disease that is HER2 amplified by ISH and 
IHC 0 or 1+ will also be enrolled (Cohort 2, N = 25; see Section 3.1). 
The primary endpoint of this study, confirmed ORR, is a direct measure of antitumor activity and 
is an acceptable endpoint that may be evaluated in a single-arm study according to the FDA 
Guidance for Industry “Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics” (December 2018). 
Standardized RECIST 1.1 criteria (Eisenhauer 2009) will be employed to evaluate disease 
responses during the study, and all imaging assessments will be submitted to an independent 
third-party imaging core laboratory to ensure consistent unbiased application of the RECIST 1.1 
criteria. Investigator-determined responses will be confirmed by repeat scans performed 4 weeks 
after initial documentation of response. Every effort should be made to confirm disease 
progression radiographically whenever possible. Only in instances where subjects appear to have 
unequivocal clinical progression and it is not possible or feasible for the subject to undergo 
radiologic assessment should investigators remove the subject from study treatment. Local 
assessment of disease response will be used for subject management and treatment decisions. To 
further assess the clinical significance of ORR in this study, DOR will be evaluated as a 
secondary endpoint. 
3.2.1. 
Method of Assigning Subjects to Treatment Groups 
This is a single-arm study that will enroll subjects into 2 separate cohorts. 
3.2.2. 
Rationale for Selection of Doses 
All subjects in the study will receive 20 mg/kg zanidatamab given IV Q2W. This dose was a 
recommended dose from the monotherapy part of the Phase 1, dose-escalation study of 
zanidatamab (ZWI-ZW25-101). 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 34 of 97 
Confidential 
 
3.2.3. 
Blinding 
This is an open-label study. 
4. 
STUDY POPULATION 
Subjects must meet all of the enrollment criteria to be eligible for this study. Eligibility criteria 
may not be waived by the investigator and are subject to review in the event of a Good Clinical 
Practice (GCP) audit and/or health regulatory authority inspection. 
4.1. 
Inclusion Criteria 
1. Histologically- or cytologically-confirmed BTC, including ICC, ECC, or GBC. 
2. Locally advanced or metastatic BTC and not eligible for curative resection, 
transplantation, or ablative therapies. 
3. Received at least 1 prior gemcitabine-containing systemic chemotherapy regimen for 
advanced disease, and experienced disease progression after or developed intolerance to 
the most recent prior therapy. For subjects who received gemcitabine in prior adjuvant or 
neoadjuvant treatment, if progression occurred < 6 months from the latter of primary 
surgical resection or completion of gemcitabine-containing adjuvant therapy, they will be 
considered as having received 1 prior line of therapy for advanced disease. 
4. Subjects must have at least 1 measurable target lesion by RECIST 1.1. Subjects who have 
received prior local therapy (embolization, chemoembolization, radiofrequency ablation, 
or radiation therapy) are eligible provided measurable disease falls outside of the 
treatment field or is within the treatment field and has shown ≥ 20% growth in size since 
post-treatment assessments. 
5. Subjects must test positive for HER2 amplification by in situ hybridization (ISH) assay at 
a central laboratory on a new biopsy or archival tissue. Note that fine needle aspirates 
(FNAs; cytology samples) and biopsies from sites of bone metastases are not acceptable. 
Testing may occur at any time after diagnosis of advanced or metastatic disease and 
before study enrollment. 
6. Male or female, ≥ 18 years of age (or the legal age of adulthood per country-specific 
regulations). 
7. ECOG PS ≤ 1. 
8. Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1.5 x 
109/L, platelet count ≥ 75 x 109/L (not requiring transfusion support), and hemoglobin 
(Hgb) ≥ 9 g/dL (subjects with chronic anemia that is supported by intermittent red blood 
cell [RBC] transfusions are eligible). 
9. Liver function: serum bilirubin ≤1.5 x the upper limit of normal (ULN) or ≤ 3 x ULN for 
subjects with Gilbert’s disease, aspartate aminotransferase (AST) ≤ 3 x ULN, and alanine 
aminotransferase (ALT) ≤ 3 x ULN. For subjects with liver involvement, AST, and 
ALT ≤ 5.0 x ULN is acceptable. 
10. Adequate cardiac function, as defined by LVEF ≥ 50%. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 35 of 97 
Confidential 
 
11. Kidney function: glomerular filtration rate (GFR) ≥ 30 mL/min as estimated by the 
Modification of Diet in Renal Disease (MDRD) equation (see Section 7.8.3). 
12. Females of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotropin (β-hCG) pregnancy test result within 3 days prior to the first dose 
of zanidatamab. Females with false positive urine test results can be enrolled if 
subsequent serum testing is negative (see Section 4.3). 
13. For female subjects of childbearing potential and for male subjects with a partner of 
child-bearing potential, willingness for the couple to use 2 methods of birth control with a 
failure rate of less than 1% per year during the study and for 12 months after the last dose 
of zanidatamab (see Section 4.3). 
14. Male subjects must agree to not donate sperm and female subjects must agree to not 
donate oocytes starting at screening and throughout the study period, and for at least 
12 months after the last dose of zanidatamab (see Section 4.3). 
15. The subject or subject’s legally acceptable representative must provide written informed 
consent. Subjects who elect to be pre-screened for HER2 status must sign a separate 
written informed consent for collection, storage, and analysis of the tumor tissue. 
4.2. 
Exclusion Criteria 
Subjects will be excluded from the study if 1 or more of the following criteria are applicable: 
1. Received systemic anti-cancer therapy within 3 weeks of the first dose of zanidatamab. 
Received radiotherapy within 2 weeks of the first dose of zanidatamab. 
2. Had major surgery within 4 weeks of the first dose of zanidatamab. 
3. Prior treatment with HER2-targeted agents. 
4. Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or 
radiation treatment for CNS metastases within 4 weeks of start of study treatment. Stable, 
treated brain metastases are allowed (defined as subjects who are off steroids and 
anticonvulsants and are neurologically stable with no evidence of radiographic 
progression for at least 4 weeks at the time of screening). 
5. Known leptomeningeal disease (LMD). If LMD has been reported radiographically on 
baseline MRI, but is not suspected clinically by the investigator, the subject must be free 
of neurological symptoms of LMD. 
6. Concurrent uncontrolled or active hepatobiliary disorders or untreated or ongoing 
complications after laparoscopic procedures or stent placement, including but not limited 
to active cholangitis, unresolved biliary obstruction, infected biloma or abscess. Any 
complications must be resolved more than 2 weeks prior to the first dose of zanidatamab. 
7. Prior or concurrent malignancy whose natural history or treatment has, in the opinion of 
the investigator or medical monitor, the potential to interfere with the safety or efficacy 
assessment of the investigational regimen. 
8. Significant acute infection or chronic infections that have not stabilized with treatment. 
9. Active hepatitis, including the following criteria: 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 36 of 97 
Confidential 
 
a 
Acute or chronic hepatitis B (Exception: subjects who are hepatitis B surface antigen 
positive are eligible if they have HBV DNA less than 500 IU/mL) 
b Infection with hepatitis C (Exception [i] subjects who have no history of curative 
viral treatment and are documented to be viral load negative are eligible; [ii] subjects 
who have completed curative viral therapy ≥ 12 weeks prior to enrollment, and viral 
load is negative are eligible) 
10. Infection with human immunodeficiency virus (HIV)-1 or HIV-2 (Exception: subjects 
with well-controlled HIV [e.g., CD4 > 350/mm3 and undetectable viral load] are eligible). 
11. Females who are breastfeeding or pregnant, and females and males planning a pregnancy. 
12. History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant 
proteins or excipients in the drug formulation of zanidatamab. 
13. Treatment with anthracyclines within 90 days before first dose of zanidatamab and/or 
total lifetime load exceeding 360 mg/m2 Adriamycin® or equivalent. 
14. Use of corticosteroids administered at doses equivalent to >15 mg per day of prednisone 
within 2 weeks of first zanidatamab dosing unless otherwise approved by the medical 
monitor. Topical, ocular, intra-articular, intranasal, and/or inhalational corticosteroids are 
permitted. 
15. Ongoing, clinically significant toxicity (Grade 2 or higher) associated with prior cancer 
therapies, with the following exceptions: 
a 
Alopecia 
b 
Congestive heart failure (CHF), which must have been ≤ Grade 1 at the time of 
occurrence and which must have completely resolved 
c 
Grade 2 peripheral sensory neuropathy 
16. QTc Fridericia (QTcF) > 470 ms. 
17. History of myocardial infarction or unstable angina within 6 months prior to enrollment, 
troponin levels consistent with myocardial infarction, or clinically significant cardiac 
disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, or 
any history of symptomatic CHF. 
18. Acute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver disease. 
19. Any other medical, social, or psychosocial factors that, in the opinion of the investigator, 
could impact safety or compliance with study procedures. 
4.3. 
Childbearing Potential and Contraception 
4.3.1. 
Definitions 
A person of childbearing potential is anyone born female who has experienced menarche and 
who has not undergone surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy) or has not completed menopause. Menopause is defined clinically as no 
menses for 12 months without an alternative medical cause. A high follicle stimulating hormone 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 37 of 97 
Confidential 
 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
According to the inclusion and exclusion criteria, pregnant or breastfeeding subjects cannot be 
included in the study, and adequate contraceptive measures should be taken to prevent female 
subjects of childbearing potential or female partners of male subjects (either of whom are of 
childbearing potential) from getting pregnant from the time of signing informed consent, during 
study participation and for at least 12 months after the last dose of study drug (see Section 4.3.2). 
Subjects will be instructed that known or suspected pregnancy occurring during this same period 
of time should be reported to the investigator, regardless of when the pregnancy was confirmed. 
If a female subject is pregnant, the investigator will immediately discontinue the subject from the 
study. Upon discontinuation, only those procedures that would not expose the subject to undue 
risk will be performed. 
In the event that a female subject or female partner of a male subject is found to be pregnant after 
inclusion in the study, the pregnancy will be followed to term with subject/partner consent, and 
the status of the mother and child will be reported to the sponsor after delivery. 
Details of the pregnancy will be recorded on the withdrawal page of the case report form (CRF), 
and a Pregnancy Report Form will be completed. 
4.3.2. 
Methods of Contraception 
The contraceptive standards and acceptable combinations of contraception methods that are 
associated with a failure rate of < 1% per year when used consistently and correctly are 
considered highly effective birth control methods per the Clinical Trial Facilitation Group 
(CTFG) 2014 guidance document: “Recommendations related to contraception and pregnancy in 
clinical trials”. These methods are detailed in Table 5. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 38 of 97 
Confidential 
 
Table 5: 
Acceptable Methods of Highly Effective Birth Control 
a 
Subjects should not simultaneously use more than one form of hormonal contraception associated with inhibition of 
ovulation (e.g., if subject is taking oral combined estrogen and progestogen containing hormonal contraception, they 
should not use another combined estrogen and progestogen or progestogen-only hormonal contraception).  
b 
Contraception methods that are considered to have low user dependency per the CTFG guidance document. 
c 
Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the 
trial participant and that the vasectomised partner has received medical confirmation of the surgical success. 
d 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with study treatment. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
 
Unacceptable methods of contraception for this clinical trial (either because they have a failure 
rate of > 1% per year or because they are considered unacceptable methods in clinical trials per 
the CTFG guidance document) are listed in Table 6. 
Table 6: 
Unacceptable Methods of Birth Control 
• 
Progestin-only hormonal contraception 
• 
Male or female condom with or without spermicide 
• 
Cap, diaphragm, or sponge with spermicide 
• 
Periodic abstinence 
• 
Withdrawal 
• 
Spermicides only 
• 
Lactational amenorrhea method (LAM) 
• 
Concomitant use of female and male condoms 
 
4.4. 
Removal of Subjects From Therapy or Assessment 
Jazz Pharmaceuticals or their designee must be notified if a subject is withdrawn from study 
treatment or from the study. The reason(s) for withdrawal must be documented in the subject’s 
medical records and CRF. 
4.4.1. 
Treatment Discontinuation 
Study treatment may be discontinued for any of the following reasons: 
• AE 
• Death 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulationa: 
o 
oral 
o 
intravaginal 
o 
transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulationa: 
o 
oral 
o 
injectable 
o 
implantableb 
• 
intrauterine device (IUD)b 
• 
intrauterine hormone-releasing system (IUS)b 
• 
bilateral tubal occlusionb 
• 
vasectomised partnerb,c 
• 
sexual abstinenced 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 39 of 97 
Confidential 
 
• Lost to follow-up 
• Withdrawal by subject 
• Physician decision (non-AE, non-progressive disease [PD]) 
• Pregnancy 
• PD (either radiographic or unequivocal clinical progression; see Section 7.2) 
• Study termination by sponsor 
• Other, non-AE 
If a subject has not received zanidatamab for more than 4 weeks due to an AE, the investigator 
should contact the medical monitor to discuss whether the subject should continue to receive 
study treatment. 
If a subject starts subsequent non-study anti-cancer therapy, study treatment must be 
discontinued before the start of the new therapy. 
At a minimum, all efforts should be made for subjects to complete the End of Treatment (EOT) 
visit (Section 6.4) and the safety follow-up visit (Section 6.5).  
Subjects who discontinue treatment with zanidatamab for reasons other than progressive disease 
or start of subsequent anticancer therapy will continue in follow-up with disease assessments 
approximately every 8 weeks after the previous scan until disease progression or start of 
subsequent anticancer therapy. Following progression or start of subsequent anticancer therapy, 
disease assessments will be discontinued, and subjects will enter long-term follow-up for 
survival status.  
4.4.2. 
Subject Withdrawal from Study 
Subjects may be discontinued from the study for any of the following reasons: 
• Lost to follow-up 
• Death 
• Withdrawal of consent 
• Study termination by sponsor 
5. 
TREATMENTS 
5.1. 
Treatments Administered 
Subjects will be treated with zanidatamab administered as monotherapy. 
5.2. 
Investigational Study Drug (Zanidatamab) 
Detailed information describing the preparation, administration, and storage of zanidatamab is 
located in the Pharmacy Manual. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 40 of 97 
Confidential 
 
5.2.1. 
Description 
Zanidatamab is a humanized bispecific antibody recognizing 2 non-overlapping epitopes of the 
ECD of the human HER2 antigen. A schematic representation of zanidatamab is shown in Figure 
2. The IgG1-like fragment crystallizable (Fc) region of zanidatamab contains complementary 
mutations in each constant heavy chain (CH) 3 domain that impart preferential pairing to 
generate a heterodimeric molecule and correspondingly disfavor formation of homodimers. 
Chain A is otherwise a normal IgG1 heavy chain and forms a fragment antigen-binding (Fab) 
arm through pairing with immunoglobulin G (IgG) Kappa light Chain A’. Chain A/A’ binds to 
ECD2 of HER2. Chain B has an IgG1-like hinge and CH2 and CH3 domains, but contains a 
single-chain variable fragment (scFv) antibody rather than a Fab arm. Chain B binds to ECD4 of 
HER2. In place of the CH1 domain it has a variable light (VL) domain, an unstructured 20 amino 
acid linker of glycine and serine residues, followed by a variable heavy (VH) domain to form an 
scFv domain. Zanidatamab is being developed as a treatment for locally advanced (unresectable) 
and/or metastatic HER2-expressing cancers. 
Figure 2: 
Structure of Zanidatamab 
Fab = fragment antigen-binding; Fc = fragment crystallizable; IgG1 = immunoglobulin G 1; scFv = single-chain 
variable fragment 
 
5.2.2. 
Dose and Administration 
All subjects must receive prophylactic treatment for potential infusion reactions prior to 
zanidatamab dosing as outlined in Section 5.2.7.1. 
Dosing for zanidatamab will be given as follows: 
• 20 mg/kg IV zanidatamab; dosing Q2W on Days 1 and 15 of each 28-day cycle (see 
Section 5.2.3 for information regarding dose modifications) 
Zanidatamab will be administered by IV infusion given over approximately 120 to 150 minutes. 
If the first 2 doses are well tolerated by a given subject, the infusion duration for that subject may 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 41 of 97 
Confidential 
 
be decreased to 90 minutes. If the next 2 doses are well tolerated, the infusion duration may be 
decreased to less than 90 minutes, however, the infusion rate should not exceed 250 mL/hour. 
Refer to the Pharmacy Manual for specific details. Zanidatamab must not be administered as an 
IV push or bolus. Zanidatamab should not be mixed with other medications. See Section 5.4 for 
guidelines for management of infusion reactions. 
Dosing is based on the subject’s actual body weight at baseline. Doses must be adjusted for 
subjects who experience a ≥ 10% change in weight from baseline. Other dose adjustments for 
changes in body weight are permitted per institutional standard. Detailed instructions for dose 
preparation are provided in the Pharmacy Manual. 
5.2.3. 
Dose Modifications 
Recommendations for management of and potential dose modifications for zanidatamab-
associated toxicity are provided in Table 7. Guidelines for management of zanidatamab-
associated left ventricular dysfunction are provided in Table 8. Guidelines for managing 
pulmonary toxicity are provided following Table 8. 
Note that there must be a minimum of 12 days between doses. Cycles will not be skipped. If a 
cycle is delayed for any reason, once the subject resumes treatment the next dose delivered will 
be considered Day 1 of the cycle that was delayed. If the Day 15 dose of a cycle is delayed by 
≥ 12 days, then that dose will be considered skipped. The next dose delivered will be Day 1 of 
the subsequent cycle. 
Table 7: 
Recommended Management and Potential Dose Modifications for 
Zanidatamab-Associated Toxicity 
Adverse Event 
Related to 
Zanidatamab 
Grade 
Action for Zanidatamab 
Nausea and/or 
vomiting 
 
Grade 1/2 
● Suggest a 5HT3 receptor antagonist until resolution of symptoms. 
● No dose modification of zanidatamab is required. 
● For breakthrough nausea or vomiting, consider adding olanzapine 5 or 10 mg daily 
for three days. For subjects already receiving olanzapine, prochlorperazine may be 
used.  
Grade 3 
● Suggest a 5HT3 receptor antagonist plus a glucocorticoid (e. g., dexamethasone); 
consider adding a NK-1 receptor antagonist to a 5HT3 receptor antagonist and 
glucocorticoids if the latter combination is not sufficient for symptom relief. 
Treatment until resolution of symptoms to ≤ Grade 1.  
● Hold zanidatamab until severity ≤ Grade 1 or pretreatment level, then resume 
zanidatamab at the same dose level  
 
 
 
 
 
 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 42 of 97 
Confidential 
 
Table 7: 
Recommended Management and Potential Dose Modifications for 
Zanidatamab-Associated Toxicity (Cont.) 
 
Adverse Event 
Related to 
Zanidatamab 
Grade 
Action for Zanidatamab 
Vomiting 
Grade 4 
● Suggest a 5HT3 receptor antagonist plus a glucocorticoid (e. g., dexamethasone); 
consider adding a NK-1 receptor antagonist to a 5HT3 receptor antagonist and 
glucocorticoids if the latter combination is not sufficient for symptom relief. 
Treatment until resolution of symptoms to ≤ Grade 1. 
● Hold zanidatamab until severity ≤ Grade 1 or pretreatment level.  
● For Grade 4 vomiting that improves to ≤ Grade 2 within 72 hours with supportive 
management, resume at the same dose level. 
● For Grade 4 vomiting lasting longer than 72 hours, permanently discontinue 
zanidatamab.  
● For recurrent Grade 4 vomiting, permanently discontinue zanidatamab. 
Diarrhea 
 
Grade 1/2 
● Oral hydration with fluid that contains water, salt, and glucose, such as broth or 
Gatorade.  
● Suggest loperamide 4 mg PO followed by 2 mg Q4H or with each loose stool until 
no diarrhea.  
● No dose modification of zanidatamab is required. 
Diarrhea 
 
Grade 3 
● Aggressive fluid hydration and clear liquid diet. 
● Loperamide 4 mg PO followed by 4 mg Q2H until resolution of diarrhea; consider 
Lomotil alternating with loperamide and/or octreotide 100 or 150 mcg 
subcutaneously Q8H for subjects with persistent diarrhea despite 48 hours of 
loperamide. If subjects are refractory to loperamide, Lomotil, and octreotide, 
gastroenterology should be consulted.  
● Hold zanidatamab until severity ≤ Grade 1 or pretreatment level. 
● When symptoms improve to ≤ Grade 1 or pretreatment level, resume zanidatamab 
at the same dose level or consider dose reduction after discussion with the medical 
monitor. 
● For recurrent Grade 3 symptoms despite maximum use of loperamide, Lomotil, 
and octreotide, zanidatamab dose reduction is mandatory. 
● For recurrent Grade 3 diarrhea lasting longer than 72 hr despite dose reduction of 
zanidatamab and maximum use of loperamide, Lomotil, and octreotide, or non-
compliance with maximum antidiarrheal therapy, permanently discontinue 
zanidatamab. 
Grade 4 
● Aggressive fluid hydration and clear liquid diet. 
● Loperamide 4 mg PO followed by 4 mg Q2H until resolution of diarrhea; consider 
Lomotil alternating with loperamide and/or octreotide 100 or 150 mcg 
subcutaneously Q8H for subjects with persistent diarrhea despite 48 hours of 
loperamide. If subjects are refractory to loperamide, Lomotil, and octreotide, 
gastroenterology should be consulted. 
● Hold zanidatamab until severity ≤ Grade 1 or pretreatment level. 
● For Grade 4 diarrhea that improves to ≤ Grade 2 within 72 hours with supportive 
management, resume upon improvement to ≤ Grade 1 or pretreatment level. 
zanidatamab dose reduction is mandatory. 
● For Grade 4 diarrhea lasting longer than 72 hours, permanently discontinue 
zanidatamab. 
● For recurrent Grade 4 diarrhea, permanently discontinue zanidatamab. 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 43 of 97 
Confidential 
 
Table 7: 
Recommended Management and Potential Dose Modifications for 
Zanidatamab-Associated Toxicity (Cont.) 
Adverse Event 
Related to 
Zanidatamab 
Grade 
Action for Zanidatamab 
Rash 
 
Grade 1/2 
● Suggest topical steroid as needed. 
● No dose modification of zanidatamab is required.  
Grade 3 
● Suggest initiation of topical steroid; if response insufficient, consider oral 
corticosteroids. Suggest wound care for skin erosions and ulcerations and to 
prevent infection.  
● Suggest analgesics for pain control if necessary. 
● If not limiting self-care activities and not associated with infection requiring 
systemic antibiotics, follow guidelines for Grades 1–2 severity. 
● If limiting self-care activities or associated with infection requiring systemic 
antibiotics, hold zanidatamab until severity ≤ Grade 1 or pretreatment level, then 
resume at the same dose. 
● For recurrence of Grade 3 symptoms limiting self-care activities or associated with 
infection requiring systemic antibiotics, despite optimal management with topical 
and/or oral corticosteroids, zanidatamab dose reduction is mandatory. 
Grade 4 
● Permanently discontinue zanidatamab. 
Other 
zanidatamab-
related AEs (other 
than IRR)a 
Grade 1/2 
● No dose modification of zanidatamab is required 
Grade 3 
● Hold zanidatamab until severity ≤ Grade 1 or pretreatment level. 
● When symptoms improve to ≤ Grade 1 or pretreatment level, resume zanidatamab 
at the same dose level. 
Grade 4 
● Grade 4 electrolyte imbalances/laboratory abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset (e.g., Grade 4 hyponatremia) do not 
require zanidatamab discontinuation. 
● For other Grade 4 AEs, permanently discontinue zanidatamab.  
AE = adverse event; IRR = infusion-related reaction; PO = by mouth; Q2H = every 2 hours; Q4H = every 4 hours; 
Q8H = every 8 hours. 
a 
Guidance for management of infusion-related reactions is provided in Section 5.2.3.1. 
 
Table 8: 
Management of Left Ventricular Dysfunction 
Left Ventricular Dysfunction 
(Regardless of Causality) 
Action for Zanidatamab 
● Absolute decrease in LVEF of ≥ 16 percentage 
points from pre-treatment baseline, or  
● LVEF below institutional limits of normal and 
absolute decrease of ≥ 10 percentage points 
below pretreatment baseline  
● Suspend dosing for at least 4 weeks 
● Repeat LVEF assessment within 4 weeks 
● Dosing may be resumed within 4 to 8 weeks if 
LVEF returns to normal limits and the absolute 
decrease is ≤ 15 percentage points from baseline; 
otherwise, permanently discontinue 
● Grade ≥ 2 (symptomatic) heart failure 
● Hold zanidatamab. Referral to a cardiologist is 
recommended. If symptomatic CHF is confirmed, 
permanently discontinue. 
CHF = congestive heart failure; LVEF = left ventricular ejection fraction. 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 44 of 97 
Confidential 
 
Pulmonary Toxicity 
Dosing with zanidatamab should be held for subjects with symptoms or findings consistent with 
Grade 2 or higher pneumonitis or interstitial lung disease (ILD) pending evaluation per 
institutional standards including radiographic imaging and pulmonary function tests as indicated. 
Zanidatamab treatment should be permanently discontinued in the event of confirmed treatment-
related Grade 2 or higher ILD. Subjects who experience any of the above-mentioned pulmonary 
toxicities should be evaluated for alternative infectious etiology and should receive prompt 
treatment per local standard of care. 
5.2.3.1. 
Infusion Reactions 
The symptoms of infusion-related reactions include fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, 
or hypertension. Severe reactions may include acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation, and cardiogenic shock. Subjects should be closely monitored 
for such reactions. Immediate access to an Intensive Care Unit or equivalent environment and 
appropriate medical therapy (including epinephrine, corticosteroids, intravenous antihistamines, 
bronchodilators, and oxygen) must be available to treat infusion-related reactions. Management 
of zanidatamab-related infusion reactions are based on the grade of symptoms as outlined in 
Table 9. 
Table 9: 
Zanidatamab Treatment Modification for Symptoms of Infusion-Related 
Reactions 
NCI-CTCAE Grade 
Treatment Modification for Zanidatamab 
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Closely monitor for 
worsening symptoms. Institute medical management as 
described in the text following this table. 
Subsequent infusions should be given at the reduced 
infusion ratea. Consider additional premedications (e.g., 
H2 blockers) for subsequent infusions. 
Grade 2 - moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, nonsteroidal anti-inflammatory 
drugs, narcotics, intravenous fluids); prophylactic 
medications indicated for ≤ 24 hours. 
Stop infusion. Infusion may be resumed at 50% of the 
previous rate once infusion-related reaction has resolved. 
Closely monitor for worsening symptoms. Proper 
medical management should be instituted as described in 
the text accompanying this table. 
Subsequent infusions should be given after 
premedication and at the reduced infusion ratea 
Consider additional premedications (e.g., H2 blockers) 
for subsequent infusions. 
Grade 3 – severe 
Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae. 
Immediately stop the infusion. Proper medical 
management should be instituted as described in the text 
accompanying this table. 
Infusion should not be restarted even if signs and 
symptoms completely resolve. With medical monitor 
approval the subject may be dosed at the next scheduled 
treatmenta. Consider additional premedications (e.g., 
H2 blockers for subsequent infusions). 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 45 of 97 
Confidential 
 
For recurrent Grade 3 reactions, permanently 
discontinue. 
Grade 4 – life-threatening 
Life-threatening consequences; urgent intervention 
indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described in the text 
following this table. 
The subject should be withdrawn from study drug 
treatment. 
Hospitalization is recommended. 
NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events 
a   Once the zanidatamab infusion rate has been decreased by 50% or suspended due to an infusion-related reaction, it may only 
be increased for subsequent infusions with medical monitor approval; premedication for subsequent infusions must be 
administered per Section 5.2.7 and may be supplemented per institutional standards. If the subject has a second infusion-
related reaction (≥ Grade 3) on the slower infusion rate, the infusion should be discontinued, and the subject should be 
withdrawn from zanidatamab treatment. 
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be 
instituted, as indicated per the type of reaction. This includes but is not limited to an 
antihistamine (e.g., diphenhydramine or equivalent), antipyretic (e.g., acetaminophen or 
equivalent), and, if considered indicated, oral (PO) or IV glucocorticoids, bronchodilators, and 
oxygen. 
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes but is not limited to 
PO or IV antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen. 
If feasible, blood samples for evaluation of tryptase, PK and/or ADA should be drawn during or 
as soon as possible after an infusion reaction.  
5.2.4. 
Storage and Handling 
Zanidatamab must be stored in a controlled location, where access is limited to only designated 
site staff. Refer to the Pharmacy Manual for detailed drug storage information. Drug 
accountability procedures are also provided in the Pharmacy Manual. 
5.2.5. 
Packaging and Labeling 
Refer to the Pharmacy Manual for packaging and labeling. 
5.2.6. 
Preparation 
Detailed drug preparation and administration instructions are provided in the Pharmacy Manual. 
5.2.7. 
Concomitant Therapy 
All prior systemic anti-cancer therapies taken from the time of diagnosis will be captured in the 
CRF. 
All medications being taken at the time of study entry should be continued as necessary and at a 
stable dose level and frequency, if possible, unless prohibited for study entry. 
For additional guidance on required and concomitant medications, investigators should refer to 
region-specific prescribing information for each agent. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 46 of 97 
Confidential 
 
5.2.7.1. 
Required Concomitant Therapy 
All subjects must receive mandatory prophylactic treatment for potential infusion reactions 30 to 
60 minutes before the start of each zanidatamab infusion. Pretreatment should include 
corticosteroids, antihistamines, and acetaminophen at the following recommended doses: 
• Corticosteroids – either hydrocortisone 100 mg IV or dexamethasone 10 mg IV or 
equivalent or per institutional guidelines 
• Antihistamines – diphenhydramine 50 mg PO or IV or per institutional guidelines 
• Acetaminophen or paracetamol – 650 to 1000 mg PO or per institutional guidelines 
If an alternative premedication regimen is thought to be required, the investigator must seek 
sponsor approval. Sponsor approval is required before implementation. 
For subjects who experience an infusion reaction despite the above premedication, other 
medication as needed per the investigator or per institutional standards including histamine-2 
receptor antagonists (H2 blockers) may be given in addition to the mandatory premedication. 
5.2.7.2. 
Allowed Concomitant Therapy 
Supportive therapy, including transfusions and bisphosphonates (e.g., Zometa®), is allowed on 
study. Supportive care treatments, including growth factors and colony-stimulating factors, are 
also allowed. Corticosteroid treatment is permitted only as follows: 
• Topical, ocular, intra-articular, intranasal, and/or inhalational corticosteroids 
• Physiologic replacement doses of systemic corticosteroids (i.e., < 15 mg/day 
prednisone) 
• As part of premedication for zanidatamab 
• For prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune 
conditions (e.g., delayed hypersensitivity reaction caused by a contact allergen 
• For acute medical conditions (higher doses permitted with medical monitor approval, 
but not to exceed 4 weeks) 
Routine prophylaxis with vaccines is generally permitted; however, live vaccines are prohibited. 
All other therapies not specifically listed in the exclusion criteria or in prohibited therapy are 
allowed. 
5.2.7.3. 
Prohibited Concomitant Therapy 
Subjects may not receive cancer-related surgery, radiotherapy, other investigational, or systemic 
anti-neoplastic therapy during the study. Chinese or other herbal medicines for the treatment of 
cancer are also prohibited. Radiation therapy under certain circumstances (e.g., palliative 
radiation therapy to certain sites [non-target sites]) may be allowed with sponsor approval. Use 
of alternative supplemental therapies is discouraged and use of any such product must be 
recorded. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 47 of 97 
Confidential 
 
5.3. 
Duration of Study Treatment 
Subjects may continue on study treatment until investigator-determined radiographic disease 
progression per RECIST 1.1, unequivocal clinical progression, unacceptable toxicity, consent 
withdrawal, physician decision, pregnancy, start of a subsequent anticancer therapy, or study 
termination by the sponsor. Every effort should be made to confirm disease progression 
radiographically. Only in instances where subjects appear to have unequivocal clinical 
progression and it is not possible or feasible for the subject to undergo radiologic assessment 
may investigators remove the subject from study treatment. 
Subjects who discontinue treatment with zanidatamab for any reason should enter the 30-day 
follow-up period, as well as survival follow-up. 
5.4. 
Management of Infusion Reactions and Other Adverse Reactions 
Management of infusion reactions and other toxicities related to or associated with zanidatamab 
is described in Section 5.2.3. Required premedications as prophylaxis for zanidatamab infusion 
reactions are described in Section 5.2.7.1. 
5.5. 
Treatment Compliance 
Zanidatamab administration will be performed by study site staff and documented in source 
documents and the CRF. 
6. 
STUDY ACTIVITIES 
AEs and concomitant medications will be recorded from Day 1 (pre-dose) through the safety 
reporting period (see Section 7.8.1.3). Any study protocol-related SAE (defined in 
Section 7.8.1.1) as well as any concomitant medications given for treatment of the SAE, should 
be recorded from the time of signing the pre-screening or main informed consent for the study. A 
schedule of events is provided in Table 1. Study activities are listed by visit in this section and 
descriptions of all study assessments are presented in Section 7. 
Guidance regarding the potential impact of COVID-19 on study enrollment and conduct is 
provided in the study manual. 
6.1. 
Optional HER2 Pre-screening Visit (After Diagnosis and Prior to 
Screening Visit) 
Subjects may be tested for HER2 status any time after diagnosis of advanced or metastatic 
disease and before study enrollment. The following assessments will be done at this optional 
visit: 
• Informed consent for collection, storage, and analysis of the tumor tissue 
• New tumor biopsy or archived tissue. Either an FFPE tissue block or a minimum of 
10 freshly cut slides are required (see the Laboratory Manual for details). FNAs 
(cytology samples) and biopsies from sites of bone metastases are not acceptable. If 
there is enough biopsy tissue to provide at least 10 additional tissue slides, next 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 48 of 97 
Confidential 
 
generation sequencing (NGS) testing can be performed, and the results shared (not 
applicable in China). 
Once a prospective subject experiences disease progression or develops intolerance to their most 
recent prior therapy, the main consent for the remaining screening assessments listed below must 
be signed. 
6.2. 
Screening Visit (Day –28 to 1) 
The screening procedures listed below will be completed within 28 days before first 
administration of study treatment (C1D1). In case a subject cannot receive their first treatment 
within the required time windows for the screening assessments, rescreening should be 
performed. 
Procedures done as part of standard of care within the 28-day window and meeting study 
requirements may be used for study purposes. 
• Informed consent 
• Medical history 
• Eligibility (per the inclusion and exclusion criteria) 
• Demographic data 
• EQ-5D-5L and BPI questionnaires; administered prior to any other assessments 
• Assessment of opioid use 
• New tumor biopsy or archived tissue (only required if not done as part of pre-
screening). Either an FFPE tissue block or a minimum of 10 freshly cut slides are 
required (see the Laboratory Manual for details). FNAs (cytology samples) and 
biopsies from sites of bone metastases are not acceptable. If there is enough biopsy 
tissue to provide at least 10 additional tissue slides, NGS testing can be performed 
and the results shared (not applicable in China). 
• Disease assessment per RECIST 1.1 (CT/MRI scans) 
• Brain scan (MRI or CT if MRI not feasible [CT with contrast unless medically 
contraindicated]) 
• Height 
• Body weight 
• Physical examination 
• ECOG PS 
• Vital signs 
• Hematology, coagulation, and serum chemistry panels (including tryptase). The 
coagulation panel must be repeated at subsequent cycles if indicated.  
• Urinalysis; must be repeated at subsequent cycles if indicated. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 49 of 97 
Confidential 
 
• Pregnancy test: urine pregnancy test performed for women of childbearing potential. 
A serum test must be performed if the urine pregnancy test is positive or equivocal. In 
the event that a urine pregnancy test is not available, a serum pregnancy test can be 
used instead. 
• Male subjects with partners of childbearing potential will be asked to confirm their 
partner is not pregnant. 
• 12-lead ECG; must be repeated at subsequent cycles if indicated 
• Echocardiogram/multigated acquisition scan (MUGA) 
• Hepatitis B surface antigen, hepatitis C antibody, and HIV tests (HIV 1/2 Ag/Ab 
combination immunoassay) 
6.3. 
Treatment Period 
6.3.1. 
Cycle 1 
6.3.1.1. 
Cycle 1 Day 1 
Prior to dosing: 
• Confirm subject eligibility per inclusion/exclusion criteria 
• Body weight 
• Physical exam (does not need to be repeated if completed for screening within the 
previous 3 days) 
• ECOG PS (does not need to be repeated if completed for screening within the 
previous 3 days) 
• Vital signs 
• Hematology (does not need to be repeated if completed for screening within the 
previous 3 days) 
• Serum chemistry (does not need to be repeated if completed for screening within the 
previous 3 days) 
• Pregnancy test: urine pregnancy test performed for women of childbearing potential. 
A serum test must be performed if the urine pregnancy test is positive or equivocal. In 
the event that a urine pregnancy test is not available, a serum pregnancy test can be 
used instead. Test does not need to be repeated if completed for screening within the 
previous 3 days. 
• Male subjects with partners of childbearing potential will be asked to confirm their 
partner is not pregnant. 
• Samples for: 
o ADA 
o ctDNA 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 50 of 97 
Confidential 
 
o HER2 ECD 
o PK  
Administer study treatment: 
• Zanidatamab administration  
Post-dose activities: 
• Vital signs (within 30 minutes of the end of the infusion) 
• Samples for PK as applicable 
6.3.1.2. 
Cycle 1 Day 2 
• Samples for PK (subjects undergoing extensive PK sampling only) 
6.3.1.3. 
Cycle 1 Day 5 
• Samples for PK (subjects undergoing extensive PK sampling only) 
6.3.1.4. 
Cycle 1 Day 15 (±2 days) 
Prior to dosing: 
• Body weight 
• Vital signs 
• Hematology 
• Serum chemistry 
• Samples for: 
− ADA 
− HER2 ECD 
− PK  
Administer study treatment: 
• Zanidatamab administration  
Post-dose activities 
• Vital signs (within 30 minutes of the end of the infusion) 
• Samples for PK 
6.3.2. 
Cycle 2 
6.3.2.1. 
Cycle 2 Day 1 (±2 days) 
Prior to dosing: 
• Body weight 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 51 of 97 
Confidential 
 
• Physical exam 
• ECOG PS 
• Vital signs 
• Hematology 
• Serum chemistry 
• Pregnancy test: urine pregnancy test performed for women of childbearing potential. 
A serum test must be performed if the urine pregnancy test is positive or equivocal. In 
the event that a urine pregnancy test is not available, a serum pregnancy test can be 
used instead. 
• Male subjects with partners of childbearing potential will be asked to confirm their 
partner is not pregnant. 
• Samples for: 
− ADA 
− PK  
Administer study treatment: 
• Zanidatamab administration  
Post-dose activities: 
• Vital signs (within 30 minutes of the end of the infusion) 
• Samples for PK 
6.3.2.2. 
Cycle 2 Day 15 (±2 days) 
Prior to dosing: 
• Body weight 
• Vital signs 
• Hematology 
• Serum chemistry 
• Samples for: 
− ADA 
− HER2 ECD 
− PK 
Administer study treatment: 
• Zanidatamab administration  
Post-dose activities: 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 52 of 97 
Confidential 
 
• Vital signs (within 30 minutes of the end of the infusion) 
• Samples for PK 
6.3.2.3. 
Cycle 2 Day 28 (±7 days) 
• EQ-5D-5L and BPI questionnaires; administered prior to any other assessments 
• Assessment of opioid use 
• Disease assessment per RECIST 1.1 (CT/MRI scans) 
• Samples for ctDNA 
6.3.3. 
Each Subsequent 28-Day Cycle 
6.3.3.1. 
Cycle 3 and Subsequent Cycles: Day 1 (±2 days) 
Prior to dosing: 
• Body weight 
• Physical exam 
• ECOG PS 
• Vital signs 
• Hematology 
• Serum chemistry 
• Pregnancy test: urine pregnancy test performed for women of childbearing potential. 
A serum test must be performed if the urine pregnancy test is positive or equivocal. In 
the event that a urine pregnancy test is not available, a serum pregnancy test can be 
used instead. 
• Male subjects with partners of childbearing potential will be asked to confirm their 
partner is not pregnant. 
• Echocardiogram/MUGA (within 7 days prior to Cycle 3 Day 1 and every 3 cycles 
thereafter [i.e., Day 1 of Cycle 6, 9, 12, etc. - 7 days]) 
• Samples for: 
− ADA (Cycles 4, 6, 8, 10, 12, 18, 24, and 36 only) 
− HER2 ECD (Cycles 4, 8, and 12 only) 
− PK (Cycles 4, 6, 8, 10, and 12 only; extensive PK sampling for 1 cycle for 
subjects participating in extensive steady-state PK schedule) 
Administer study treatment: 
• Zanidatamab administration  
Post-dose activities: 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 53 of 97 
Confidential 
 
• Vital signs (within 30 minutes of the end of the infusion) 
• Samples for PK (Cycles 4, 6, 8, 10, and 12 only) 
6.3.3.2. 
Cycle 3 and Subsequent Cycles: Day 15 (±2 days) 
Prior to dosing: 
• Body weight 
• Vital signs 
• Hematology 
• Serum chemistry  
• Samples for PK (for 1 cycle at Cycle 4 or later, only for subjects participating in 
extensive steady-state PK schedule) 
Administer study treatment: 
• Zanidatamab administration  
Post-dose activities: 
• Vital signs (within 30 minutes of the end of the infusion) 
6.3.4. 
Every 8 Weeks (±7 days); Timed from Cycle 1 Day 1 
• EQ-5D-5L and BPI questionnaires; administered prior to any other assessments 
• Assessment of opioid use 
• Disease assessment per RECIST 1.1 (CT/MRI scans; include brain scan for subjects 
with history or clinical suspicion of brain metastases; CT with contrast unless 
medically contraindicated). 
6.4. 
End of Treatment Visit 
The EOT visit will be performed for subjects who are withdrawn from treatment for any reason 
and will take place as soon as possible after a subject permanently stops study treatment (within 
7 days after treatment discontinuation) unless delayed due to an AE. EOT evaluations must be 
performed before initiation of a new therapy. The date the subject met criteria for study treatment 
discontinuation and the reason for study treatment discontinuation will be recorded. 
The following procedures will be performed at the EOT visit: 
• Optional tumor biopsy at disease progression for subjects who provide additional 
consent 
• EQ-5D-5L and BPI questionnaires; administered prior to any other assessments 
• Assessment of opioid use 
• Disease assessment per RECIST 1.1 (CT/MRI scans; not required if 4 weeks since 
previous scan; include brain scan for subjects with history or clinical suspicion of 
brain metastases; CT with contrast unless medically contraindicated) 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 54 of 97 
Confidential 
 
• Physical examination 
• ECOG PS 
• Vital signs 
• Hematology 
• Serum chemistry 
• Pregnancy test: urine pregnancy test performed for women of childbearing potential. 
A serum test must be performed if the urine pregnancy test is positive or equivocal. In 
the event that a urine pregnancy test is not available, a serum pregnancy test can be 
used instead. 
• Male subjects with partners of childbearing potential will be asked to confirm their 
partner is not pregnant. 
• 12-lead ECG 
• Echocardiogram/MUGA (not required if 3 months since last scan) 
• Samples for: 
− ADA 
− ctDNA (only at time of disease progression, if applicable) 
− HER2 ECD (only at time of disease progression, if applicable) 
− PK (only required if subject has completed less than 6 months of treatment) 
 
6.5. 
Safety Follow-up (Approximately 30 Days After the Last Dose of 
Study Drug) 
Approximately 30 days after the last dose of study drug, all subjects will have a follow-up visit, 
which will include the following assessments: 
• Disease assessment per RECIST 1.1 (CT/MRI scans; only required if feasible, and 
last scan showed unconfirmed PR/CR and performed 4 weeks prior; include brain 
scan for subjects with history or clinical suspicion of brain metastases; CT with 
contrast unless medically contraindicated) 
• Physical examination 
• ECOG PS 
• Vital signs 
• Hematology 
• Serum chemistry 
• Pregnancy test: urine pregnancy test performed for women of childbearing potential. 
A serum test must be performed if the urine pregnancy test is positive or equivocal. In 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 55 of 97 
Confidential 
 
the event that a urine pregnancy test is not available, a serum pregnancy test can be 
used instead. 
• Male subjects with partners of childbearing potential will be asked to confirm their 
partner is not pregnant. 
• ADA samples (not required if ≤ 2 weeks since last sample) 
Additionally, all AEs should continue to be followed until significant changes return to baseline, 
the event stabilizes (recovering/resolving) or is no longer considered clinically significant by the 
investigator, or the subject dies, is lost to follow-up, or withdraws consent, or study closure. 
6.6. 
Efficacy Follow-up (Every 8 Weeks) 
Subjects who discontinue treatment with zanidatamab for reasons other than progressive disease 
or start of subsequent anticancer therapy will continue in follow-up with disease assessments 
(per RECIST 1.1 [CT/MRI scans; include brain scan for subjects with history or clinical 
suspicion of brain metastases; CT with contrast unless medically contraindicated]) approximately 
every 8 weeks (±7 days) after the previous scan until disease progression or start of subsequent 
anticancer therapy. Responses that are initially observed during this follow-up period should be 
confirmed with disease assessment 4 weeks (+7 days) later. Following progression or start of 
subsequent anticancer therapy, disease assessments will be discontinued, and subjects will enter 
long-term follow-up for survival status.  
6.7. 
Survival Follow-Up 
Subjects will be followed for survival after discontinuation of study treatment via telephone 
calls, medical records, and/or clinic visits approximately every 3 months (± 14 days; 
month = 30 days) after the last follow-up visit or as directed by the sponsor until death, lost to 
follow-up, withdrawal of consent, study completion, or study termination by the sponsor. 
Subsequent anti-cancer therapies initiated during follow-up will also be collected, if available. 
7. 
STUDY ASSESSMENTS 
A schedule of events is provided in Table 1. 
7.1. 
Screening/Baseline Assessments 
Only subjects who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study. 
Subject medical history includes a thorough review of significant past medical history, current 
conditions, and any treatment for prior malignancies and response to prior treatment. 
Tumor biopsies will be collected from all subjects at either pre-screening or screening and 
processed as FFPE tissues to assess HER2 amplification, protein expression by IHC, and 
exploratory biomarkers of response. Archival tumor tissue may also be used. Subjects may be 
tested for HER2 status any time after diagnosis of advanced or metastatic disease and before 
study enrollment. An ISH assay is being developed as an investigational use only (IUO) reagent 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 56 of 97 
Confidential 
 
for determining eligibility. An IHC assay is being developed an IUO reagent for assigning 
subjects to Cohort 1 or 2. 
All samples will be run in a central laboratory under Clinical Laboratory Improvement 
Amendments (CLIA) guidelines. DNA and RNA may be isolated from tissue biopsies for 
characterizing gene expression and somatic mutations associated with response. 
Tests for hepatitis B surface antigen, hepatitis C antibody, and HIV will be performed at 
screening. For female subjects of childbearing potential, screening for pregnancy will be 
performed at screening. These tests may be done using the blood samples taken for clinical 
chemistry. A urine pregnancy test is also acceptable. 
7.2. 
Response/Efficacy Assessments 
Tumor response will be evaluated at the visits outlined in the schedule of assessments (Table 1) 
based on CT and/or MRI scans (using the same methodology for each scan of the same subject; 
CT with contrast unless medically contraindicated) of the chest, abdomen, and pelvis plus 
additional areas of known or suspected tumor involvement including the brain for subjects with 
history or clinical suspicion of brain metastases. All CT and MRI imaging will be performed 
locally and submitted for centralized independent review. Additional imaging, such as nuclear 
bone scans, may be done as appropriate at the discretion of the investigator. 
Disease response will be assessed according to RECIST 1.1 (Eisenhauer 2009) by ICR (primary 
endpoint) and investigator (secondary endpoint); responses are to be confirmed 4 weeks 
following initial documentation of objective response by investigator. Investigator assessment of 
response will be used for all treatment-related decisions. 
Unequivocal clinical progression is defined as worsening or re-emergence of pre-existing 
symptoms relating to underlying cancers (e.g., increase in disease-related pain), or emergence of 
new symptoms that cannot be attributed to study drug toxicities or alternative causes. A marked 
deterioration in ECOG performance status may also indicate unequivocal clinical progression. 
Every effort should be made to confirm disease progression radiographically. Only in instances 
where subjects appear to have unequivocal clinical progression and it is not possible or feasible 
for the subject to undergo radiologic assessment should investigators remove the subject from 
study treatment. 
Subjects who discontinue treatment with zanidatamab for reasons other than progressive disease 
or start of subsequent anticancer therapy will continue in follow-up with disease assessments 
approximately every 8 weeks after the previous scan until disease progression or start of 
subsequent anticancer therapy. Responses that are initially observed during this follow-up period 
should be confirmed with disease assessment 4 weeks later. Following progression or start of 
subsequent anticancer therapy, disease assessments will be discontinued, and subjects will enter 
long-term follow-up for survival status.  
Subjects’ clinical data must be available for CRF source verification. 
7.3. 
Pharmacokinetic Assessments 
Venous blood samples for measurement of serum concentrations of zanidatamab will be drawn 
at selected timepoints as specified in the PK assessment schedules. The actual date and time 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 57 of 97 
Confidential 
 
(24-hour clock time) of each sampling will be recorded in the subject’s source document at the 
site. 
The first 10 subjects enrolled in China and first 20 suitable subjects enrolled in the rest of world 
(suitability determined by the medical monitor) will be assigned to the more extensive PK 
schedule (Table 2). Further subjects will be then assigned to the sparse PK schedule (peak-
trough, Table 3). Extensive PK for 1 cycle at steady state (Cycle 4 or later; Table 4) will be done 
for the first 10 suitable subjects in China who reach Cycle 4 and the first 20 suitable subjects in 
the rest of the world who reach Cycle 4 (suitability determined by the medical monitor). 
The sampling window for each timepoint is presented in Table 2, Table 3, and Table 4. 
Deviations from planned sampling windows will be assessed before database lock for the impact 
on PK and may be excluded from timepoint summaries of PK concentrations. Actual time will be 
used for derivation of PK parameters. 
Serum concentrations of zanidatamab will be measured as a function of time post-dosing. PK 
parameters to be estimated include the following: 1) for single (first) dose: maximum 
concentration (Cmax), time to maximum concentration (tmax), area under the serum concentration-
time curve from zero to the last measurable concentration (AUC0-t), terminal elimination rate 
constant (λz), half-life (t1/2), area under the serum concentration-time curve from zero to infinity 
(AUC0-∞), serum clearance (CL), volume of distribution (Vd), etc.; and 2) for multiple doses: area 
under the serum concentration-time curve from zero to the end of dosing interval (AUCtau), 
average concentration (Cave) for Dose 1, Cmax and minimum concentration (Cmin) (trough) for 
subsequent doses, accumulation index, fluctuation ratio, steady state concentration (Css), and 
attainment of steady state. 
Complete instructions for PK sample collection, processing, handling, and shipment will be 
provided in the Laboratory Manual. 
If a subject experiences an AE that results in an unscheduled visit or meets SAE criteria, a blood 
sample for the measurement of serum concentrations of zanidatamab should be collected if less 
than 24 hours have elapsed since the last dose of zanidatamab, if possible. The sample will be 
recorded as unscheduled timepoint and may be also used in PK parameters derivation using 
actual time. An additional sample may also be drawn in the event of an infusion reaction. 
7.4. 
Biomarker Studies 
Blood and tumor tissue samples will be taken at selected timepoints specified in the assessment 
schedule (Table 1) for assessment of biomarkers. Biomarkers may include but are not limited to 
ctDNA, tumor tissue DNA and RNA, HER2 ECD, CA19-9, and post-treatment HER2 tumor 
status.  
Tumor biopsies or archival tissues will be assessed for HER2 amplification, protein expression 
by IHC, and exploratory biomarkers of response. DNA and RNA may be isolated from tissue 
biopsies for characterizing gene expression and somatic mutations associated with response. 
Tumor samples will also be used for developing candidate companion diagnostics (CDx) for this 
study, including but not limited to CDx bridging assays. 
Only the biomarkers specified above will be tested on samples collected in Mainland China. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 58 of 97 
Confidential 
 
Complete instructions for biomarker sample collection, processing, handling, and shipment will 
be provided in the Laboratory Manual. 
7.5. 
Immunogenicity Assessments 
Blood samples to test for antibodies to zanidatamab will be obtained at selected timepoints 
specified in the assessment schedule (Table 1). Blood samples for ADAs will be taken before the 
start of the zanidatamab infusion. All ADA blood sample collection timepoints during the first 
2 treatment cycles coincide with a pre-dose PK sample timepoint. If a subject terminates early 
from the clinical trial, all efforts will be made to collect blood samples to test for antibodies to 
zanidatamab unless consent has been withdrawn. 
If a subject experiences an AE that results in an unscheduled visit or meets SAE criteria, a blood 
sample to test for antibodies to zanidatamab should be collected if less than 24 hours have 
elapsed since the last dose of zanidatamab, if possible. The sample will be recorded as 
unscheduled timepoint. An additional sample may also be drawn in the event of an infusion 
reaction. 
The immunogenicity testing will be performed in 3 steps as follows: screening assay (Tier 1), 
confirmation assay (Tier 2), and titration (Tier 3). Only samples positive in the screening assay 
will be tested in confirmation and only samples positive in the confirmation assay will be further 
titrated to determine the titer of ADA. 
For any samples that are confirmed positive for anti-zanidatamab antibody, there may be 
additional testing done to characterize domain specificity (T2a) and possibly neutralizing 
activity. 
Complete instructions for ADA sample collection, processing, handling, and shipment will be 
provided in the Laboratory Manual. 
Additional sample handling, processing, storage, labeling, and shipping instructions will be 
provided to the site in the Laboratory Manual. 
7.6. 
Biospecimen Repository 
For subjects who provide additional consent, remaining de-identified unused blood and/or tissue 
will be retained by the sponsor and used for future research (not applicable in China), including 
but not limited to the evaluation of targets for novel therapeutic agents. No germ-line DNA 
testing will be performed. Blood and tissue samples donated for future research will be retained 
for a period of up to 5 years after study closure, or as permitted by local regulations. If additional 
consent is not provided, any remaining biological samples will be destroyed following study 
completion. 
7.7. 
Quality of Life and Disease-Related Pain Assessments 
The EQ-5D 5-L questionnaire will be used to assess overall quality of life. If possible, the 
questionnaire should be completed before any other procedures at the study visits noted in the 
schedule of events (see Table 1). The EQ-5D-5L consists of a visual assessment scale to assess 
overall health status and the 5-dimensional score assesses health status in terms of mobility, self- 
care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 response 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 59 of 97 
Confidential 
 
levels: no problems, slight problems, moderate problems, severe problems, and unable 
to/extreme problems. 
The Brief Pain Inventory (BPI) short form will be used to assess disease-related pain. The BPI 
rapidly assesses the severity of pain and its impact on functioning and is widely used in clinical 
trials. The BPI pain items assess worst pain in the last 24 hours, least pain in the last 24 hours, 
pain on average, and pain right now. The BPI interference items include general activity, mood, 
walking ability, normal work, relations with other people, sleep, and enjoyment of life. 
7.8. 
Safety Assessments 
Assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including AESIs, SAEs, clinical laboratory tests, concomitant medications, 
including opioids, over-the-counter medications, and herbal therapies, and physical examination 
findings. Other safety assessments include evaluation of ECOG PS, vital signs, ECGs, and 
echocardiogram/MUGA. 
Safety and study conduct will be monitored by an IDMC, who will be tasked with monitoring the 
safety of participants through regular and/or ad hoc meetings (see Section 9.4.12). 
7.8.1. 
Adverse Events 
7.8.1.1. 
Definitions 
Adverse Event 
According to the International Council for Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 Code of Federal Regulations (CFR) 312.32, IND 
Safety Reporting, an AE is any untoward medical occurrence in a subject or clinical 
investigational subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. 
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events CRF: 
• From the time of signing the pre-screening or main informed consent for the study 
through Cycle 1 Day 1 pre-dose, only study protocol-related SAEs should be 
recorded. A protocol-related SAE is defined as an untoward medical event occurring 
as a result of a protocol mandated procedure. 
• All AEs (regardless of relationship to study drug) should be recorded from Cycle 1 
Day 1 (during and post-dose) through the end of the safety reporting period (see 
Section 7.8.1.3). Complications that occur in association with any procedure (e.g., 
biopsy) should be recorded as AEs whether or not the procedure was protocol 
mandated. 
• Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded. 
• In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in a SAE, 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 60 of 97 
Confidential 
 
or results in study termination or interruption/discontinuation of study treatment. 
When recording an AE resulting from a laboratory abnormality, the resulting medical 
condition rather than the abnormality itself should be recorded (e.g., record “anemia” 
rather than “low hemoglobin”). 
Serious Adverse Events 
An AE should be classified as an SAE if it meets 1 of the following criteria: 
Fatal: 
AE resulted in death 
Life threatening: 
The AEs placed the subject at immediate risk of death. This 
classification does not apply to an AE that hypothetically might 
cause death if it were more severe. 
Hospitalization: 
The AE resulted in hospitalization or prolonged an existing in-
patient hospitalization. Hospitalizations for elective medical or 
surgical procedures or treatments planned before the signing of 
informed consent in the study or routine check-ups are not SAEs by 
this criterion. Admission to a palliative unit or hospice care facility 
is not considered to be a hospitalization. Hospitalizations or 
prolonged hospitalizations for scheduled therapy of the underlying 
cancer or study target disease need not be captured as SAEs. 
Disabling/ 
incapacitating: 
An AE that resulted in a persistent or significant incapacity or 
substantial disruption of the subject’s ability to conduct normal life 
functions. 
Congenital 
anomaly or birth 
defect: 
An adverse outcome in a child or fetus of a subject exposed to the 
molecule or study treatment regimen before conception or during 
pregnancy. 
Important medical 
event: 
The AE did not meet any of the above criteria but could have 
jeopardized the subject and might have required medical or surgical 
intervention to prevent 1 of the outcomes listed above or involves 
suspected transmission via a medicinal product of an infectious agent. 
Adverse Event Severity 
AE severity should be graded using the NCI-CTCAE, version 5.0. These criteria are provided in 
the study manual. 
AE severity and seriousness are assessed independently. “Severity” characterizes the intensity of 
an AE. “Serious” is a regulatory definition and serves as a guide to the sponsor for defining 
regulatory reporting obligations (see definition for SAEs, above). 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 61 of 97 
Confidential 
 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to the study drug should be evaluated by the investigator using the 
following criteria: 
Related: 
There is evidence to suggest a causal relationship between the drug 
and the AE, such as: 
● A single occurrence of an event that is uncommon and known 
to be strongly associated with drug exposure (e.g., angioedema, 
hepatic injury, Stevens-Johnson Syndrome) 
● One or more occurrences of an event that is not commonly 
associated with drug exposure, but is otherwise uncommon in the 
population exposed to the drug (e.g., tendon rupture) 
There is a reasonable possibility of a relationship based on facts, 
evidence, and/or arguments to suggest a causal relationship, rather 
than a relationship cannot be ruled out. 
Unrelated: 
Another cause of the AE is more plausible (e.g., due to underlying 
disease or occurs commonly in the study population), or a temporal 
sequence cannot be established with the onset of the AE and 
administration of the study treatment, or a causal relationship is 
considered biologically implausible. 
 
7.8.1.2. 
Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during subject 
questioning, discovered during physical examination, laboratory testing and/or other means by 
recording them on the CRF and/or SAE form, as appropriate. 
Eliciting Adverse Events 
An open-ended or non-directed method of questioning should be used at each study visit to elicit 
the reporting of AEs. 
Recording Adverse Events 
The following information should be recorded on the Adverse Events CRF: 
• Description including onset and resolution dates 
• Whether it met SAE criteria 
• Severity 
• Relationship to study treatment or other causality 
• Outcome 
The investigator should use precise medical terminology when recording AEs or SAEs. Avoid 
colloquialisms and abbreviations. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 62 of 97 
Confidential 
 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events) should be identified by 
their primary cause. For example, if severe diarrhea is known to have resulted in dehydration, it 
is sufficient to record only diarrhea as an AE or SAE. However, medically important events that 
may be linked and/or separated in time should be recorded as independent events on the eCRF. 
For example, if severe hemorrhage leads to renal failure, both events should be recorded 
separately on the eCRF. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject evaluation 
time points. Such an event should be recorded only once unless its severity increases or 
decreases (in which case it should be recorded again). 
A recurrent AE is one that occurs and resolves between subject evaluation time points, but then 
subsequently recurs. All recurrences of the AE should be recorded as separate events. 
Diagnosis vs. Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual symptoms. 
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 
symptom is a medically confirmed component of a diagnosis as evidenced by standard medical 
textbooks. If any aspect of a sign or symptom does not fit into a classic pattern of the diagnosis, 
report the individual symptom as a separate AE. 
Recording Serious Adverse Events 
For SAEs, record the event(s) on both the CRF and an SAE form. The following should be 
considered when recording SAEs: 
• Death is an outcome of an event. The primary cause of death as assessed by the 
investigator should be recorded and reported as the SAE term on both an SAE form 
and CRF. If the cause of death is truly unknown, then “Death of Unknown Cause” 
can be used as the SAE term for the initial report. Once the cause of death is known, 
the event term should be updated on a follow-up report. 
• For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
Progression of the Underlying Cancer 
Clinical manifestations of disease progression that meet the criteria for a SAE must be reported. 
Do not use the term ‘disease progression’ alone when reporting SAEs, because it is too 
nonspecific. Symptoms of disease progression that meet the criteria for an SAE must be reported. 
When possible, report the specific disease (clinical) manifestation of the progression (e.g., 
‘malignant pleural effusion’, ‘spinal bone metastases’, ‘lymphadenopathy’, ‘brain metastases’). 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 63 of 97 
Confidential 
 
Pregnancy 
Notification to Drug Safety: Complete a Pregnancy Report Form for all pregnancies that occur 
from the time of first study drug dose until 12 months after the last dose of study drug including 
any pregnancies that occur in the partner of a male study subject. Only report pregnancies that 
occur in a male subject’s partner if the estimated date of conception is after the male subject’s 
first study drug dose. Email or fax to the sponsor’s Drug Safety Department within 24 hours of 
becoming aware of a pregnancy. All pregnancies will be monitored for the full duration; all 
perinatal and neonatal outcomes should be reported.  
Collection of data on the CRF: All pregnancies (as described above) that occur within 30 days of 
the last dose of study drug will also be recorded on the Adverse Events CRF. 
Abortion, whether therapeutic or spontaneous, should be reported as an SAE. Congenital 
anomalies or birth defects, as defined by the “serious” criterion above (see definitions 
Section 7.8.1.1) should be reported as SAEs. 
7.8.1.3. 
Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from the start of study drug dosing on 
Cycle 1 Day 1 to 30 days after the last dose of study drug. However, all study protocol-related 
SAEs are to be recorded from the time of signing the pre-screening or main informed consent for 
the study. All SAEs that occur after the safety reporting period and are considered related to 
prior zanidatamab study drug treatment in the opinion of the investigator should also be reported 
to the sponsor. 
All AEs (including SAEs and AESIs) will be followed until significant changes return to 
baseline, the event stabilizes (recovering/resolving) or is no longer considered clinically 
significant by the investigator, or the subject dies, is lost to follow-up, or withdraws consent, or 
study closure.  
7.8.1.4. 
Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, investigators are to report the event to the 
sponsor, regardless of the relationship of the event to the study treatment regimen. 
For initial SAE reports, available case details are to be recorded on an SAE form. At a minimum, 
the following should be included: 
• Subject number 
• Date of event onset 
• Description of the event 
• Investigator assessment of causality 
• Study treatment 
The completed SAE form is to be emailed or faxed to the sponsor’s Drug Safety Department 
within 24 hours (see email or fax number specified on the SAE report form). 
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes available. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 64 of 97 
Confidential 
 
7.8.1.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The sponsor will report all SAEs to regulatory authorities as required per local regulatory 
reporting requirements. 
7.8.2. 
Adverse Events of Special Interest 
AESIs are infusion-related reactions, non-infectious pulmonary toxicities, and cardiac events of 
absolute decrease in LVEF of ≥ 10 percentage points from pretreatment baseline and absolute 
value < 50%, and/or grade ≥ 2 heart failure. AESIs should be recorded as AEs and reported as 
SAEs when appropriate.  
Additional data related to AESIs may be collected in the CRF. 
7.8.3. 
Clinical Laboratory Tests 
Samples for clinical laboratory tests will be obtained at selected timepoints specified in the 
assessment schedule (Table 1). 
Clinical laboratory analyses will be performed at local laboratories. Any abnormalities in any of 
the laboratory parameters will be judged in relation to the reference ranges from the laboratory 
and to the clinical relevance assessed by the investigator. 
The following hematology parameters will be determined: 
• Hemoglobin 
• Hematocrit 
• White blood cell (WBC) count (total and differential) 
• RBC count 
• Platelet count 
• Mean corpuscular volume 
• Mean cell hemoglobin (MCH) 
• MCH concentration 
Coagulation parameters such as prothrombin time (PT), international normalized ratio (INR), 
and activated partial thromboplastin time (aPTT) will also be required at specified timepoints. 
The following clinical chemistry parameters will be measured: 
• Creatinine, urea (or blood urea nitrogen [BUN]) 
• AST 
• ALT 
• Alkaline phosphatase 
• Lactate dehydrogenase 
• Total bilirubin 
• Albumin 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 65 of 97 
Confidential 
 
• Total protein 
• Sodium 
• Potassium 
• Chloride 
• Glucose 
• Uric acid 
• Calcium 
• Magnesium 
• Tryptase (if test is available, only at screening and within 24 hours of an infusion 
reaction) 
The estimated GFR should be calculated using the MDRD equation as applicable, with serum 
creatinine (Scr) reported in mg/dL as follows: 
• GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if 
African American) 
Urine will be screened for pH, glucose, ketones, blood, protein, and microscopy (if indicated). 
For female subjects of childbearing potential, pregnancy tests will be performed at screening and 
at predetermined timepoints specified in the assessment schedule (see Table 1). These tests may 
be done using the blood samples taken for clinical chemistry. A urine pregnancy test is also 
acceptable. 
7.8.4. 
Vital Signs 
Vital signs measurements include heart rate, blood pressure, respiratory rate, and temperature. 
Vital signs will be recorded at selected timepoints specified in the assessment schedule (Table 1) 
and performed in a standardized manner (i.e., after the subject has rested in the sitting position 
for 5 minutes). Post-dose assessments should be done within approximately 30 minutes after the 
end of the zanidatamab infusion. 
7.8.5. 
Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. Height will only be measured 
at screening. 
7.8.6. 
ECOG Performance Status 
ECOG PS will be assessed at selected timepoints specified in the assessment schedule (Table 1). 
ECOG PS scores are described in Appendix A. 
7.8.7. 
Electrocardiogram 
12-lead ECGs will be recorded at selected timepoints specified in the assessment schedule 
(Table 1) and as clinically indicated. The ECG will be recorded after at least a 10-minute rest. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 66 of 97 
Confidential 
 
The date and an overall interpretation of the ECG will be recorded in the CRF. The interpretation 
of the ECG will be assessed as normal or abnormal, and if abnormal as clinically significant or 
not. If the ECG is considered abnormal and clinically significant, the abnormality must be 
recorded in the CRF. At least the following parameters should be assessed: heart rate, PR 
interval, QRS complex, and QTcF. See Appendix C for the equation to calculate QTcF. 
7.8.8. 
Echocardiogram/MUGA 
Echocardiograms or MUGA scans are recorded at selected timepoints specified in the assessment 
schedule (Table 1). Echocardiograms or MUGAs will be recorded locally and will be assessed 
for an estimate of the ejection fraction. The same method must be used throughout the study. 
Management of left ventricular dysfunction is described in Section 5.2.3. 
7.9. 
Appropriateness of Measurements 
The RECIST 1.1 criteria used to assess efficacy in this study are widely used and generally 
recognized as reliable, accurate, and relevant to the disease condition. 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. 
Pharmacokinetic assessments are also common in clinical studies to help characterize dose-
exposure-response relationships. 
Immunogenicity is commonly assessed for biologics; therefore, standard tests will be performed 
to detect the possible presence of specific antibodies to zanidatamab. 
8. 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
8.1. 
Audit and Inspection 
Study centers and study documentation may be subject to Quality Assurance audits during the 
course of the study by the sponsor or its nominated representative. In addition, inspections may 
be conducted by regulatory authorities or the institutional review board (IRB)/independent ethics 
committee (IEC) at their discretion. 
The investigator must permit the IRB/IEC, the sponsor’s auditors, and representatives from 
regulatory authorities to have direct access to all study-related documents and pertinent hospital 
or medical records for confirmation of data contained within the CRFs. Subject confidentiality 
will be protected at all times. 
8.2. 
Monitoring 
Data for each subject will be recorded on a CRF. Data collection must be completed for each 
subject who signs an ICF and undergoes any screening assessment. 
In accordance with GCP and ICH guidelines, the study monitor will carry out source document 
verification at regular intervals to ensure that the data collected in the CRF are accurate and 
reliable. The frequency of monitoring visits will be determined by the rate of subject recruitment. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 67 of 97 
Confidential 
 
A clinical monitoring plan will detail the tasks to be completed at each monitoring visit. This 
will include the following at a minimum: 
• Site monitoring procedures including review of the ICF, source document review, 
source data verification, and review of CRF data 
• AE and SAE reporting 
• Investigational product receipt, ordering, preparation and administration, storage, 
documentation, accountability, dosing compliance, and return/destruction 
The monitoring visits also provide the sponsor with the opportunity to ensure the investigator’s 
obligations and all applicable ICH or health authority regulation requirements are being fulfilled. 
The investigator must permit the monitor direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the CRFs. Subject 
confidentiality will be protected at all times. 
8.3. 
Data Management and Coding 
Study centers will enter data directly into an electronic data capture system by completing the 
CRF via a secure internet connection. Data entered into the eCRF must be verifiable against 
source documents at the study center. Changes to data previously entered into the electronic data 
capture system will be recorded in the audit trail and will be FDA 21 CFR Part 11 compliant 
and/or meet other region-specific electronic records regulatory requirements. 
Adverse events and pre-existing conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) and medications will be coded using the World Health 
Organization (WHO) Drug Dictionary. Missing or inconsistent data will be queried in the 
electronic database to the investigator for clarification. Subsequent modifications to the database 
will be documented. 
8.4. 
Drug Accountability 
Each site will verify their inventory of study drug supplies throughout the study and verify that 
study drug is received intact and in the correct amounts. The monitor may check the study 
supplies at each study center at any time during the study. 
The study monitor will ensure that the site has correctly documented the amount of the study 
drug received, dispensed, and returned on the dispensing log. A full drug accountability log will 
be maintained at the study center at all times. All discrepancies must be accounted for and 
documented. 
9. 
DATA ANALYSIS METHODS 
9.1. 
Statistical Hypotheses 
This is a single-arm, open-label study. No statistical hypotheses will be tested. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 68 of 97 
Confidential 
 
9.2. 
Determination of Sample Size 
This study will enroll approximately 100 subjects: approximately 75 subjects in Cohort 1 and 
approximately 25 subjects in Cohort 2. No formal sample size calculations were performed. 
Approximately 75 subjects will be enrolled in Cohort 1 to evaluate the primary endpoint of 
confirmed ORR for the primary analysis of efficacy. The 2-sided Clopper-Pearson exact 
binomial 95% confidence intervals (CIs) that could be observed with this sample size are listed 
in Table 10. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 69 of 97 
Confidential 
 
Table 10: 
Clopper-Pearson 95% Confidence Intervals for N = 75 Subjects 
Confirmed ORR 
95% CI 
Percent 
Responses 
Lower 
Upper 
20.0% 
15 
11.7% 
30.8% 
25.3% 
19 
16.0% 
36.7% 
30.7% 
23 
20.5% 
42.4% 
36.0% 
27 
25.2% 
47.9% 
40.0% 
30 
28.9% 
52.0% 
45.3% 
34 
33.8% 
57.3% 
50.7% 
38 
38.9% 
62.4% 
Approximately 25 subjects will be enrolled in Cohort 2 to evaluate the primary endpoint of 
confirmed ORR as a secondary analysis of efficacy. The 2-sided Clopper-Pearson exact binomial 
95% CIs that could be observed with a sample size of 25 subjects are listed in Table 11. 
Table 11: 
Clopper-Pearson 95% Confidence Intervals for N=25 Subjects 
Confirmed ORR 
95% CI 
Percent 
Responses 
Lower 
Upper 
20.0% 
5 
6.8% 
40.7% 
24.0% 
6 
9.4% 
45.1% 
28.0% 
7 
12.1% 
49.4% 
32.0% 
8 
15.0% 
53.5% 
36.0% 
9 
18.0% 
57.5% 
40.0% 
10 
21.1% 
61.3% 
44.0% 
11 
24.4% 
65.1% 
48.0% 
12 
27.8% 
68.7% 
With a sample size of 100 subjects (Cohorts 1 and 2 combined), the probabilities of detecting 
1 or more treatment-emergent adverse events (TEAEs) for various frequencies of occurrence in 
this population are listed in Table 12. 
Table 12: 
Probabilities of Detecting ≥ 1 Adverse Event 
Frequency of Adverse Event 
Binomial Probability 
0.1% 
0.10 
1% 
0.63 
5% 
0.99 
 
9.3. 
Analysis Sets 
For the purposes of analysis, the subject analysis sets are defined in Table 13. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 70 of 97 
Confidential 
 
Table 13: 
Subject Analysis Sets 
Analysis Set 
Description 
Enrolled 
All participants who sign the main study informed consent, were eligible for the study, 
and received approval to enroll at the end of Screening. 
Safety 
All safety evaluable subjects enrolled in Cohorts 1 and 2. 
A subject is considered safety evaluable if they received any amount of zanidatamab. 
Efficacy 
The following Efficacy Analysis Sets will be evaluated for this study: 
• 
Cohort 1 (Primary) - Includes all safety evaluable subjects enrolled in 
Cohort 1. The primary analysis of efficacy will be performed using this 
analysis set. 
• 
Cohort 2 - Includes all safety evaluable subjects enrolled in Cohort 2. 
Response Evaluable 
The following Response Evaluable Analysis Sets will be evaluated for this study: 
• 
Cohort 1 - Includes all response evaluable subjects enrolled in Cohort 1 
• 
Cohort 2 - Includes all response evaluable subjects enrolled in Cohort 2 
Response Evaluable includes all subjects in the safety analysis set with measurable 
disease and at least 1 evaluable post-baseline disease assessment (per RECIST 1.1) or 
who discontinued study treatment due to death or unequivocal clinical progression. 
In the event of significant discordance between the set of subjects identified as 
response evaluable by the investigator and ICR, the following 2 Response Evaluable 
Analysis Sets may be evaluated for each of the above cohorts: 
• 
ICR Response Evaluable 
• 
Investigator Response Evaluable 
 
9.4. 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will be written and finalized prior to database lock and will 
provide additional details regarding the statistical methods, endpoints, and analyses to be 
performed, and deviations from the statistical analysis methods described in the protocol. This 
section is a summary of the planned statistical analyses of the primary, secondary, and 
exploratory endpoints. Any changes to the methods described in the final SAP will be described 
and justified in the clinical study report. 
9.4.1. 
General Considerations 
The final analysis of the study will be conducted after the final database lock for the study. 
9.4.1.1. 
Randomization and Blinding 
This is a single-arm, open-label study; therefore, no randomization or blinding will be 
performed. 
9.4.1.2. 
Adjustments for Covariates 
No adjustments for covariates will be performed. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 71 of 97 
Confidential 
 
9.4.1.3. 
Handling of Dropouts and Missing Data 
For the purpose of cohort assignment, subjects missing IHC results will be assigned to Cohort 1. 
Further details for the handling of missing, unused, or spurious data will be described in the 
SAP. 
9.4.1.4. 
Multicenter Studies 
No formal comparisons between sites will be performed. 
9.4.1.5. 
Multiple Comparisons and Multiplicity 
No adjustments for multiple comparisons will be performed. 
9.4.1.6. 
Data Transformations and Derivations 
Data transformations, conventions, and derivations will be detailed in the SAP. 
9.4.1.7. 
Examination of Subgroups 
Subgroup analysis of the primary endpoint by BTC histology type will be performed. Selected 
secondary efficacy endpoints may also be evaluated by this subgroup. 
9.4.2. 
Subject Disposition 
An accounting of study subjects by disposition will be tabulated and the number of subjects in 
each analysis set will be summarized. Subjects who discontinue study treatment and subjects 
who withdraw from the study will be summarized with reason for discontinuation or withdrawal. 
9.4.3. 
Subject Characteristics 
Baseline demographic and disease characteristics will be summarized using counts and 
percentages for categorical variables and summary statistics (e.g., mean, quartiles, standard 
deviation, and range) for continuous variables. 
9.4.4. 
Treatment Compliance 
Not applicable. 
9.4.5. 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) Version 2009 or higher, and listed and summarized by preferred term using counts 
and percentages. Multiple occurrences of the same medication within a subject will be 
summarized only once. 
The change from baseline in opioid use will be summarized over time and at the time of a 
subject’s best overall response. 
9.4.6. 
Efficacy Analyses 
The endpoints listed below will be evaluated based on both the ICR and the investigator 
RECIST 1.1 response assessments. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 72 of 97 
Confidential 
 
The primary analysis of efficacy will evaluate these endpoints and the primary endpoint, 
confirmed ORR, for subjects in the Cohort 1 Primary Efficacy Analysis Set. Secondary analyses 
of these endpoints will evaluate these endpoints for the Cohort 2 Efficacy Analysis Set (see 
Section 9.3). If a meaningful treatment effect is observed in Cohort 2, a pooled efficacy analysis 
of Cohort 1 + 2 may be performed. 
9.4.6.1. 
Best Overall Response 
Best overall response (BOR) is defined as the BOR per RECIST 1.1 prior to any of the following 
occurring for a subject: 
• Receipt of non-protocol specified anticancer therapy 
• Documented disease progression 
• Death from any cause 
• Subject withdrawal of consent 
Confirmed BOR requires confirmation of CR or PR a minimum of 4 weeks from the initial 
response. 
BOR and confirmed BOR will be summarized using counts and percentages. 
9.4.6.2. 
Objective Response Rate 
Objective response is defined as achieving a BOR of CR or PR per RECIST 1.1. The proportion 
of subjects with an objective response and the corresponding exact binomial 95% CI will be 
calculated. 
Confirmed objective response is defined as achieving a confirmed BOR of CR or PR per 
RECIST 1.1. The primary endpoint for this study is the confirmed ORR based on the ICR 
response assessments evaluated for the Cohort 1 Primary Efficacy Analysis Set. A secondary 
endpoint of confirmed ORR will also be computed based on the investigator response 
assessments. For each endpoint, the proportion of subjects with a confirmed objective response 
and the corresponding exact binomial 95% CI will be calculated. 
9.4.6.3. 
Progression-free Survival 
PFS is defined as the time from the first dose of study treatment to the date of documented 
disease progression (per RECIST 1.1), clinical progression, or death from any cause. 
Unequivocal clinical progression is defined as worsening or re-emergence of pre-existing 
symptoms relating to underlying cancers (e.g., increase in disease-related pain), or emergence of 
new symptoms that cannot be attributed to study drug toxicities or alternative causes. A marked 
deterioration in ECOG performance status may also indicate unequivocal clinical progression. 
Subjects who are alive and have not progressed at the time of the analysis will be censored at the 
time of their last tumor assessment that was a CR, PR, or SD. Details of the censoring scheme 
for this analysis will be described in the SAP. 
Kaplan-Meier plots and estimates of the quartiles and their corresponding 95% CI will be 
computed. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 73 of 97 
Confidential 
 
9.4.6.4. 
Disease Control Rate 
Disease control is defined as a best response of CR, PR, or SD per RECIST 1.1. The proportion 
of subjects who achieve disease control and the corresponding exact binomial 95% CI will be 
calculated. 
9.4.6.5. 
Duration of Response 
DOR is defined as the time from the first objective response (CR or PR) to documented PD per 
RECIST 1.1, clinical progression, or death from any cause. Only subjects who achieve a 
confirmed response in the Safety Analysis Set will be included in the analysis. Details of the 
censoring scheme for this analysis will be described in the SAP. 
Kaplan-Meier plots and estimates of the quartiles and their corresponding 95% CI will be 
computed. 
In addition, the proportion of subjects with a DOR  16 weeks and the corresponding exact 
binomial 95% CI will be calculated. 
9.4.6.6. 
Overall Survival 
OS is defined as the time from the first dose of study treatment until the date of death from any 
cause. Subjects who are alive at the time of analysis or were lost to follow-up will be censored at 
the date they were last known to be alive (i.e., right censored). Details of the censoring scheme 
for the analysis of OS and imputation methods for partial or missing dates of death or last contact 
will be described in the SAP. 
Kaplan-Meier plots and estimates of the quartiles and their corresponding 95% CI will be 
computed. 
9.4.7. 
Pharmacokinetic Analyses 
Serum concentrations of zanidatamab will be measured as a function of time post-dosing. PK 
parameters to be estimated include the following: 1) for single (first) dose: Cmax, tmax, AUC0-t, λz, 
t1/2, AUC0-∞, CL, Vd, etc.; and 2) for multiple doses: AUCtau, Cave for Dose 1, Cmax and Cmin 
(trough) for subsequent doses, accumulation index, fluctuation ratio, Css, and attainment of 
steady state. 
The following PK parameters will be determined for steady-state extensive PK sampling: 
AUCtau,ss, Cave,ss, Cmin,ss, Cmax,ss, λz, t1/2, and Vz.  
9.4.8. 
Immunogenicity Analyses 
If applicable, the occurrence of ADAs will be summarized using counts and percentages by 
zanidatamab dose level and nominal timepoint. Titers for confirmed positive ADA will be 
summarized using descriptive statistics (n, arithmetic mean, geometric mean, median, standard 
deviation, range, coefficient of variance). The duration and time of onset of anti-drug antibodies 
may also be summarized using descriptive methods. 
All immunogenicity analyses will be based on the Safety Analysis Set. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 74 of 97 
Confidential 
 
9.4.9. 
Biomarker Analyses 
Potential biomarkers will be summarized using descriptive statistics (i.e., n, arithmetic mean, 
geometric mean, median, standard deviation, range, coefficient of variance). Details will be 
described separately in the SAP. 
9.4.10. 
Safety Analyses 
The endpoints listed below will be evaluated for the Safety Analysis Set. 
9.4.10.1. Extent of Exposure 
Zanidatamab exposure will be summarized using counts and percentages for categorical 
variables and summary statistics (mean, median, standard deviation, and range) for continuous 
variables. 
Information to be summarized includes duration of exposure, relative dose intensity (%), the 
total frequency of and reasons for delayed and prematurely discontinued infusions, and the 
number treatment cycles initiated. 
9.4.10.2. Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical study subject administered a 
medicinal product which does not necessarily have a causal relationship with this treatment. All 
AEs will be coded by the Sponsor to standard “preferred terms” and system organ classifications 
(SOC) using MedDRA. Severity will be graded by study investigators using NCI-CTCAE v5.0. 
TEAEs are defined as events with an onset during or after receipt of the first dose of 
zanidatamab and up to and including 30 days after the last dose but prior to the start of a new 
anti-cancer therapy. 
The frequency of TEAEs will be summarized by preferred term and SOC using counts and 
percentages. Multiple occurrences of the same AE within a subject will be summarized only 
once at the most severe grade level for the time frame under consideration. For summaries by 
severity, only the worst grade for an AE will be counted for a particular subject. AEs occurring 
prior to the first dose of zanidatamab or more than 30 days after the last dose of zanidatamab will 
be excluded from summaries but included in data listings. In addition, treatment-related AEs and 
AEs which lead to premature discontinuation of study treatment will summarized. 
9.4.10.3. Deaths and Serious Adverse Events 
The frequency of deaths will be summarized using counts and percentages. By-subject listings of 
deaths will also be produced. 
The frequency of SAEs will be summarized by SOC and preferred term using counts and 
percentages. Treatment-related SAEs will also be summarized. 
9.4.10.4. Clinical Laboratory Results 
Laboratory results will be graded using NCI-CTCAE v5.0 and summarized by laboratory test 
and toxicity grade using counts and percentages. For each laboratory test, only the worst (i.e., 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 75 of 97 
Confidential 
 
highest) toxicity grade will be counted for subjects with multiple toxicities within a time period 
(including scheduled and unscheduled assessments). 
9.4.10.5. Cardiac Function 
The frequency of ECG abnormalities (e.g., heart rate, PR interval, QRS complex, and QTcF) will 
be summarized using counts and percentages. In addition, the percentage of subjects with LVEF 
< 50% and ≥ 50% and with an absolute decrease ≥ 10 percentage points from baseline LVEF 
will be summarized. 
The frequency of QTc interval increases from baseline (< 30 msec, 30–60 msec, and > 60 msec) 
and the frequency of QTc interval prolongations ≥ 470 msec during the treatment period will 
each be summarized using counts and percentages. For both endpoints, the worst value for each 
subject during the treatment period will be summarized. 
9.4.10.6. Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be summarized 
using descriptive statistics (i.e., mean, median, standard deviation, and range). 
9.4.10.7. ECOG Performance Status 
ECOG PS over time will be listed by subject. The baseline status, worst status post-baseline, and 
status at EOT will be summarized using counts and percentages. 
9.4.10.8. Quality of Life and Disease-Related Pain Analyses 
PRO based on the EQ-5D-5L will be summarized over time with descriptive statistics by visit, 
using the Safety Analysis Set. In addition, the change from baseline in BPI domain scores will be 
summarized over time and at the time of a subject’s best overall response. 
9.4.11. 
Timing of Analyses 
The primary analysis of efficacy will be performed approximately 6 months after the last subject 
has been enrolled in Cohort 1 of the study. 
9.4.11.1. Interim Analyses 
No interim analyses will be performed. 
9.4.12. 
Independent Data Monitoring Committee 
Safety and study conduct will be monitored throughout the study by an IDMC. The committee is 
tasked with monitoring the safety of participants in this study through regular and/or ad hoc 
meetings. An IDMC meeting will be held after the first 25 subjects have received at least 1 dose 
of zanidatamab. After the first IDMC meeting, subsequent meetings will be held quarterly to 
review cumulative safety data to identify any potential new safety signals. An additional IDMC 
meeting will be held at least 28 days after the tenth subject enrolled in China has received 1 dose 
of zanidatamab to review safety. The IDMC will be responsible for making recommendations to 
the sponsor as to appropriate study direction; further details will be provided in the IDMC 
charter. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 76 of 97 
Confidential 
 
10. 
INFORMED CONSENT, ETHICAL REVIEW, AND 
REGULATORY CONSIDERATIONS 
10.1. 
Institutional Review Board/Independent Ethics Committee 
Before initiation of the study at each study center, the protocol, the ICF, other written material 
given to the subjects, and any other relevant study documentation will be submitted to the 
appropriate IRB/IEC. Written approval or favorable opinion of the study and all relevant study 
information must be obtained before the study center can be initiated. Any necessary extensions 
or renewals of IRB/IEC approval/favorable opinion must be obtained for changes to the study 
such as amendments to the protocol, the ICF or other study documentation. The written approval 
of the IRB/IEC together with the approved ICF must be filed in the study files. 
The investigator will report promptly to the IRB/IEC any new information that may adversely 
affect the safety of the subjects or the conduct of the study. The investigator will submit written 
summaries of the study status to the IRB/IEC as required. On completion of the study, the 
IRB/IEC will be notified that the study has ended. 
10.2. 
Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the participating 
countries, according to local/national requirements, for review and approval before the beginning 
of the study. On completion of the study, the regulatory authorities will be notified that the study 
has ended, as required. 
10.3. 
Ethical Conduct of the Study 
The investigator(s) and all parties involved in this study must conduct the study in accordance 
with the protocol, and in adherence to the ethical principles based on the Declaration of Helsinki 
and GCP, the applicable ICH guidelines, and the applicable national, regional, and local laws and 
regulatory requirements. 
10.4. 
Informed Consent 
The process of obtaining informed consent must be in accordance with applicable regulatory 
requirement(s) and must adhere to GCP. 
The investigator is responsible for ensuring that no subject undergoes any study-related 
examination or activity before that subject has been presented with the risks and benefits and 
given written informed consent to participate in the study, unless the procedure was done as part 
of standard of care. Pre-screening of HER2 status, after the subject consents to allow the central 
laboratory analysis/review of HER2 status, is allowed before written informed consent for all 
other study procedures is given. 
The investigator or designated personnel will inform the subject of the objectives, methods, 
anticipated benefits and potential risks and inconveniences of the study in simple terms, using 
the IRB/IEC-approved ICF. The subject will be given every opportunity to ask for clarification 
of any points he or she does not understand and, if necessary, ask for more information. At the 
end of the interview, the subject will be given ample time to consider the study. Subjects who 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 77 of 97 
Confidential 
 
choose to participate will be required to sign and date the ICF. After dated signatures are 
obtained, the ICF will be kept and archived by the investigator in the investigator’s study file. A 
signed and dated copy of the subject ICF will be provided to the subject or their legally 
authorized representative. 
It should be emphasized that the subject may refuse to enter the study or to withdraw from the 
study at any time, without consequences for their further care or penalty or loss of benefits to 
which the subject is otherwise entitled. Subjects who refuse to give or who withdraw written 
informed consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study, a new ICF will be submitted to the IRB(s)/IEC(s) (and 
regulatory authorities, if required). The study subjects will be informed about this new 
information and reconsent will be obtained. 
10.4.1. 
Subject Confidentiality 
Monitors, auditors, and other authorized agents of the sponsor and/or its designee, the 
IRB(s)/IEC(s) approving this research, and the US FDA, as well as that of any other applicable 
agency(ies), will be granted direct access to the study subjects’ original medical records for 
verification of clinical study procedures and/or data, without violating the confidentiality of the 
subjects to the extent permitted by the law and regulations. In any presentations of the results of 
this study or in publications, the subjects’ identity will remain confidential. 
All personal data collected and processed for the purposes of this study should be managed by 
the investigator and his/her staff with adequate precautions to ensure confidentiality of those 
data, and in accordance with the Health Insurance Portability and Accountability Act (HIPAA 
1996) and applicable national and/or local laws and regulations on personal data protection and 
consistent with the ICFs or authorizations from the study subjects. Furthermore, CRFs and other 
documents to be transferred to the sponsor should be completed in strict accordance with the 
instructions provided by the sponsor, including the instructions regarding the coding, de- 
identification, or pseudonymization of subject identities. 
10.5. 
Study Documentation and Records Retention 
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced. After completion of the study (end of study defined as 
the date of the last visit of the last subject), all documents and data relating to the study will be 
kept in an orderly manner by the investigator in a secure study file. This file will be available for 
inspection by the sponsor or its representatives. 
Essential documents should be retained for whichever is the longest of the following: 
• Two years after the final marketing approval 
• At least 2 years since the discontinuation of clinical development of the 
investigational product 
• The time period required by the applicable law or regulatory requirements. 
It is the responsibility of the sponsor to inform the study center when these documents no longer 
need to be retained. The investigator must contact the sponsor before destroying any study-


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 78 of 97 
Confidential 
 
related documentation. In addition, all subject medical records and other source documentation 
will be kept for the maximum time permitted by the hospital, institution, or medical practice. 
10.6. 
Clinical Trial Agreement 
Payments by the sponsor to investigators and institutions conducting the study, requirements for 
investigators’ insurance, the publication policy for clinical trial data, and other requirements are 
specified in the Clinical Trial Agreement. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 79 of 97 
Confidential 
 
11. 
REFERENCES 
A. Vogel, V. S., A. Hollebecque, G. Vaccaro, D. Melisi, R. Al-Rajabi, A.S. Paulson, M.J. Borad, 
D. Gallinson, A.G. Murphy, D. Oh E. Dotan, D.V. Catenacci, E. Van Cutsem, C.F. Lihou, H. 
Zhen, L. Féliz, G.K. Abou-Alfa (2019). "FIGHT-202: A Phase 2 Study Of Pemigatinib In 
Patients (PTS) With Previously Treated Locally Advanced or Metastic 
Cholangiocarcinoma(CCA)." Annals of Oncology 30. 
Abou-Alfa, G. K., et al. (2019). "A global, phase III, randomized, double-blind study of 
ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an 
isocitrate dehydrogenase 1 (IDH1) mutation." Annals of Oncology 30: 872-873. 
Arai, Y., et al. (2014). "Fibroblast growth factor receptor 2 tyrosine kinase fusions define a 
unique molecular subtype of cholangiocarcinoma." Hepatology 59(4): 1427-1434. 
Bang, Y. J., et al. (2010). "Trastuzumab in combination with chemotherapy versus chemotherapy 
alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer 
(ToGA): a phase 3, open-label, randomised controlled trial." Lancet 376(9742): 687-697. 
Eckel, F. and R. M. Schmid (2007). "Chemotherapy in advanced biliary tract carcinoma: a 
pooled analysis of clinical trials." Br J Cancer 96(6): 896-902. 
Eisenhauer, E. A., et al. (2009). "New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1)." Eur J Cancer 45(2): 228-247. 
Galdy, S., et al. (2017). "HER2/HER3 pathway in biliary tract malignancies; systematic review 
and meta-analysis: a potential therapeutic target?" Cancer Metastasis Rev 36(1): 141-157. 
Javle, M., et al. ( 2015). "HER2/neu-directed therapy for biliary tract cancer." J Hematol Oncol 
8:58. 
Kiguchi, K., et al. (2001). "Constitutive expression of ErbB-2 in gallbladder epithelium results in 
development of adenocarcinoma." Cancer Res 61(19): 6971-6976. 
Lamarca, A., et al. (2019). "ABC-06 | A randomised phase III, multi-centre, open-label study of 
active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy 
(ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers 
(ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy." Journal of 
Clinical Oncology 37(15_suppl): 4003-4003. 
Meric-Bernstam, F., et al. (2019). "453PDSafety, anti-tumour activity, and biomarker results of 
the HER2-targeted bispecific antibody ZW25 in HER2-expressing solid tumours." Annals of 
Oncology 30(Supplement_5). 
Meric-Bernstam, F., et al. (2019). "Advances in HER2-Targeted Therapy: Novel Agents and 
Opportunities Beyond Breast and Gastric Cancer." Clin Cancer Res 25(7): 2033-2041. 
Moasser, M. M. (2007). "The oncogene HER2: its signaling and transforming functions and its 
role in human cancer pathogenesis." Oncogene 26(45): 6469-6487. 
Nakazawa, K., et al. (2005). "Amplification and overexpression of c-erbB-2, epidermal growth 
factor receptor, and c-met in biliary tract cancers." J Pathol 206(3): 356-365. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 80 of 97 
Confidential 
 
Nam, A. R., et al. (2016). "Therapeutic implication of HER2 in advanced biliary tract cancer." 
Oncotarget 7(36): 58007-58021. 
Okusaka, T., et al. (2010). "Gemcitabine alone or in combination with cisplatin in patients with 
biliary tract cancer: a comparative multicentre study in Japan." Br J Cancer 103(4): 469-474. 
Peck, J., et al. (2012). "HER2/neu may not be an interesting target in biliary cancers: results of 
an early phase II study with lapatinib." Oncology 82(3): 175-179. 
PEMAZYRE®. Wilmington (DE): Incyte Corporation; 2020. Package insert. Available from: 
www.accessdata.fda.gov/drugsatfda_docs/label/2020/213736s000lbl.pdf. 
Ramanathan, R. K., et al. (2009). "A phase II study of lapatinib in patients with advanced biliary 
tree and hepatocellular cancer." Cancer Chemother Pharmacol 64(4): 777-783. 
Schramm, A., et al. (2015). "Targeted Therapies in HER2-Positive Breast Cancer - a Systematic 
Review." Breast Care (Basel) 10(3): 173-178. 
Slamon, D. J., et al. (2001). "Use of chemotherapy plus a monoclonal antibody against HER2 for 
metastatic breast cancer that overexpresses HER2." N Engl J Med 344(11): 783-792. 
Treekitkarnmongkol, W. and T. Suthiphongchai (2010). "High expression of ErbB2 contributes 
to cholangiocarcinoma cell invasion and proliferation through AKT/p70S6K." World J 
Gastroenterol 16(32): 4047-4054. 
Tsavaris, N., et al. (2004). "Weekly gemcitabine for the treatment of biliary tract and gallbladder 
cancer." Invest New Drugs 22(2): 193-198. 
Valle, J., et al. (2010). "Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer." 
N Engl J Med 362(14): 1273-1281. 
Valle, J. W., et al. (2017). "New Horizons for Precision Medicine in Biliary Tract Cancers." 
Cancer Discov 7(9): 943-962. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 81 of 97 
Confidential 
 
APPENDIX A. ECOG PERFORMANCE STATUS SCALE 
 
ECOG 
Score 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 82 of 97 
Confidential 
 
APPENDIX B. INVESTIGATOR SIGNATURE PAGE 
Investigator Statement and Signature 
I have read the attached protocol entitled A Phase 2b, open-label, single-arm study of 
zanidatamab (ZW25) monotherapy in subjects with advanced or metastatic HER2-amplified 
biliary tract cancers. 
I, the undersigned, have read and understood the protocol specified above and agree on its 
content. I agree to perform and conduct the study as described in the protocol and in accordance 
with the relevant laws/regulations and standards outlined in the Clinical Trial Agreement. 
 
 
 
 
 
 
 
Investigator Signature 
Date 
Investigator Name, Printed 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 83 of 97 
Confidential 
 
APPENDIX C. QTCF EQUATION 
QTcF (duration of QT interval using Fridericia’s correction) should be calculated using the 
following equation: 
 
Where QT = duration of QT interval, RR = duration of RR interval, and s=seconds 
 
 
 
 
 
 
 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 84 of 97 
Confidential 
 
APPENDIX D. DOCUMENT HISTORY 
 
Version 
Date 
Original 
13-Feb-2020 
Amendment 1 
26-Apr-2020 
China-specific Amendment 1  
23-Jul-2020 
Amendment 2 (including changes in China-specific Amendment 1) 
Amendment 3 
21-Apr-2021 
08-Sep-2023 
 
 
 
 
 
 
 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 85 of 97 
Confidential 
 
Summary of Changes in Amendment 3 
Section(s) 
Change 
Rationale 
Global 
• Updated name and organizational 
affiliation of medical monitor  
• Changed name and address of Sponsor 
(Rest of World) from Zymeworks Inc. to 
Jazz Pharmaceuticals, Inc. 
• Added information for Sponsor’s US 
Representative 
• Added JZP598 as a synonym for 
zanidatamab 
• Added EU CT number 
Administrative changes. Incorporated the most 
current Sponsor and Medical Monitor information, 
which has changed since the last amendment as a 
result of Jazz Pharmaceuticals, Inc’s acquisition of 
zanidatamab from Zymeworks, Inc.  


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 86 of 97 
Confidential 
 
Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Title page and page headers Updated date and amendment number 
To update the information for Amendment 2 
Title page 
Updated medical monitor information 
Administrative change 
Throughout protocol 
Minor clarifications/corrections 
To provide clarity and consistency 
Throughout 
Changed “ZW25” to “zanidatamab” 
Administrative change 
Section 1.2 
Section 1.4 
Section 3.2 
Added information on a recently approved 
therapy for bile duct cancer and recently 
approved HER2-targeted therapies 
To provide current information 
Synopsis  
Section 3.1 
Section 4.1 
Revised Inclusion Criterion 3 pertaining to prior 
chemotherapy regimens 
Clarification 
Synopsis  
Section 4.1 
Revised description of women of childbearing 
potential in Inclusion Criterion 13, and replaced 
list of contraception methods with reference to 
appropriate section of protocol 
To make language consistent with Inclusion 
Criterion 12, at the request of a health authority 
To avoid duplication 
Synopsis 
Section 4.2 
Revised Exclusion Criterion 6 to specify 
exclusion of subjects with infected biloma rather 
than any biloma 
To ensure subjects are not excluded unnecessarily 
Synopsis 
Section 4.2 
Revised Exclusion Criterion 7 to apply to any 
malignancy, not just invasive malignancy 
To make the criterion more straightforward 
Synopsis 
Section 4.2 
Revised Exclusion Criterion 15 so that Grade 2 
peripheral sensory neuropathy is an exception to 
the exclusion of clinically significant toxicity 
(Grade 2 or higher) associated with prior cancer 
therapies 
To ensure subjects are not excluded unnecessarily, as 
many subjects would have received prior treatment 
with cisplatin or oxaliplatin and may have 
neuropathy associated with that treatment 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 87 of 97 
Confidential 
 
Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Synopsis 
Table 1 
Section 3.1 
Figure 1 
Section 4.4.1 
Section 6.6 
Section 7.2 
Radiographic efficacy assessments are to 
continue for subjects who discontinue treatment 
with zanidatamab for reasons other than 
progressive disease or start of subsequent 
anticancer therapy. These assessments will 
continue in follow-up with disease assessments 
approximately every 8 weeks (±7 days) after the 
previous scan until disease progression or start 
of subsequent anticancer therapy. Responses 
that are initially observed should be confirmed 
with disease assessment 4 weeks (+7 days) later. 
Following disease progression or start of 
subsequent anticancer therapy, disease 
assessments will be discontinued, and subjects 
will enter long-term follow-up for survival 
status. 
To enable accurate determination of duration of 
response 
Table 1 
Section 6.2 
Section 6.3.4 
Section 6.4 
Section 6.5 
Section 6.6 
Section 7.2 
Added option for screening brain scan by CT if 
MRI not feasible, and specified that subjects 
with history or clinical suspicion of brain 
metastases should have repeat MRI or CT at 
time of all tumor restaging. CT is to be 
performed with contrast unless medically 
contraindicated. 
To allow flexibility for assessments and obtain 
information on possible brain metastases 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 88 of 97 
Confidential 
 
Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Synopsis 
Section 3.1 
Section 7.8.2 
Adverse events of special interest are modified 
to include: infusion-related reactions, non-
infectious pulmonary toxicities, and cardiac 
events of absolute decrease in LVEF 
≥ 10 percentage points from pretreatment 
baseline and absolute value < 50%, and/or grade 
≥ 2 heart failure 
For consistency across the zanidatamab program 
Section 5.2.7.1 
Added that any alternative premedication 
regimen must be approved by Sponsor before 
implementation 
For consistency with synopsis 
Table 1 
Section 6.3.3.1 
Clarified that MUGA/echocardiogram should be 
performed every 3 cycles, within 7 days prior to 
Day 1 of the cycle 
Clarification of timing 
Table 1 
Section 6.2 
Section 6.3.1.1 
Section 6.3.2.1 
Section 6.3.3.1 
Section 6.4 
Section 6.5 
For visits at which female subjects of 
childbearing potential have a pregnancy test, 
male subjects with partners of childbearing 
potential will be asked to confirm their partner 
is not pregnant 
To ensure reporting of any pregnancy in partners of 
male study subjects 
Table 2, Table 3 
PK assessment windows are widened for certain 
timepoints 
For the convenience of study subjects 
Synopsis 
Table 2 
Section 7.3 
Increased the total number of subjects to 
undergo initial extensive PK sampling from 16 
to 30 
To ensure adequate data is obtained to characterize 
PK 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 89 of 97 
Confidential 
 
Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Synopsis 
Table 1 
Table 4 
Section 6 
Section 7.3 
Section 9.4.7 
Added extensive PK sampling at steady state 
(Cycle 4 or later) for the first 10 suitable 
subjects in China who reach Cycle 4 and first 
20 suitable subjects in the rest of the world who 
reach Cycle 4 (suitability determined by the 
medical monitor) 
To enable collection of additional extensive PK data 
in subjects who have received at least 4 cycles of 
zanidatamab plus combination chemotherapy to 
provide information on steady-state PK 
Synopsis 
Section 3.1 
Section 7.4 
Post-treatment HER2 tumor status is added as a 
biomarker assessment 
To provide information about the effect of treatment 
on HER2 tumor status 
Synopsis 
Table 1 
Section 3.1 
Section 7.4 
 
 
 
 
Synopsis 
Section 3.1 
Section 7.4 
Only specified biomarkers will be tested on 
samples collected in Mainland China 
To comply with health authority guidelines 
Section 4.3.1 
Removed follow-up for any baby born to a 
female subject or female partner of a male 
subject who became pregnant during the study 
There is no mechanism for collecting and storing this 
information 
Section 4.3.2 
Table 5 
Clarified that subjects should not simultaneously 
use more than one form of hormonal 
contraception associated with inhibition of 
ovulation 
At the request of a health authority 
Section 5.2.2 
Removed option for 60-minute infusion, but 
added option for infusion duration of less than 
90 minutes provided maximum infusion rate is 
not exceeded 
Maximum infusion rate is 250 mL/hour, and it is 
unlikely that infusion volume would be less than 
250 mL 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 90 of 97 
Confidential 
 
Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Section 5.2.3 
Table 7 
Revised guidance for management of potential 
zanidatamab-associated toxicities, including 
dose modifications for nausea/vomiting, 
diarrhea, rash, and other toxicities 
To clarify guidance for managing potential 
zanidatamab-related AEs, including recommended 
zanidatamab dose modifications for severe AEs of 
vomiting, diarrhea, rash, and other toxicities 
Section 5.2.3, Table 8 
Section 5.2.3.1, Table 9 
Revised guidance for management of LVEF 
dysfunction and infusion-related reactions 
To align with program-level assessment of cardiac 
risk and infusion reactions 
Section 5.2.3 
Provided guidance for management of 
pulmonary toxicity 
To provide guidance to the investigator in the event 
of pulmonary toxicity 
Section 5.2.3.1 
Section 6.2 
Section 7.8.3 
Added assessment of tryptase at screening and 
within 24 hours of an infusion-related reaction, 
if the test is available 
To obtain information on the nature of the infusion-
related reaction 
Section 5.2.7 
Added statement referring investigators to 
region-specific prescribing information for 
additional guidance on required and 
concomitant medications 
To support compliance with prescribing information 
Section 5.2.7.2 
Added the following statement: “Routine 
prophylaxis with vaccines is generally permitted; 
however, live vaccines are prohibited.” 
To provide further guidance to sites about vaccines 
Section 6 
Added statement that guidelines to follow 
regarding the effect of COVID-19 on study 
conduct and enrollment are provided in the 
study manual 
COVID-19 may affect study enrollment and conduct, 
and these effects vary by region and country, so 
specific COVID-19 guidelines are provided in the 
study manual 
Section 6.1, Section 6.2 
Added option for next generation sequencing 
and sharing of those results if an additional 
10 tissue slides are provided (not applicable in 
China) 
Results of next generation sequencing may provide 
information that would inform treatment decisions, 
which would provide a benefit to the subject 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 91 of 97 
Confidential 
 
Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Table 1 
Section 6.4 
The timing of the end-of-treatment visit is 
changed from within 7 days after the last dose to 
within 7 days after treatment discontinuation 
(unless delayed due to an AE) 
Due to the timing of disease assessments, a decision 
to discontinue treatment could occur at a point in the 
cycle at which it would not be possible to perform 
the end-of-treatment visit within 7 days of the last 
dose  
Section 7.1 
Removed collection of current medications 
during screening 
The only concomitant medications to be collected 
during screening are those used to treat study 
protocol-related SAEs, if applicable 
Section 7.5 
Specified that only samples positive in the 
confirmation assay would be further titrated to 
determine titer of ADA 
Clarification 
Section 7.6 
Specified that the future use of remaining blood 
and/or tissue samples for subjects who provided 
additional consent would not be applicable in 
China 
To comply with health authority guidelines 
Section 7.8 
Specified that over-the-counter medications and 
herbal remedies would be collected as 
concomitant medications 
To ensure complete collection of all concomitant 
medications taken by subjects 
Section 7.8.1 
Removed the time requirement of ≥ 24 hours 
hospitalization for an AE to be classified an 
SAE 
The 24-hour period is not a requirement, and it is 
more conservative to classify any AE resulting in 
hospitalization as an SAE 
Section 7.8.1 
Changed descriptor of SAE criteria category 
from “medically significant” to “important 
medical event”  
To align terminology 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 92 of 97 
Confidential 
 
Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Section 7.8.1.2 
Clarified reporting of SAEs associated with 
disease progression and death of unknown 
cause, and added instructions for reporting AEs 
occurring secondarily to other events and for 
reporting persistent and recurring AEs 
To encourage sufficient detail when reporting of AEs 
related to progression of the underlying malignancy  
To ensure consistent AE reporting across study sites 
Section 7.8.1.2 
Removed reference to “accidental” abortion 
It is redundant to include both accidental and 
spontaneous abortion 
Synopsis 
Table 1 
Section 6.5 
Section 7.8.1.3 
Follow-up will be the same for all AEs, i.e., 
SAEs, AESIs, and non-serious AEs will all be 
followed until significant changes return to 
baseline, the event stabilizes 
(recovering/resolving) or is no longer 
considered clinically significant by the 
investigator, or the subject dies, is lost to 
follow-up, or withdraws consent, or study 
closure 
To obtain accurate information on the duration, 
reversibility, and resolution of AEs 
Synopsis 
Section 7.8.1.3 
The safety reporting period is changed to from 
the start of study drug dosing to 30 days after 
the last dose of study drug regardless of 
subsequent anticancer therapy 
To ensure full collection of safety information 
Synopsis 
Table 1 
Section 6 
Section 7.8.1.1 
Section 7.8.1.3 
During the screening period (from time of 
signing the pre-screening or main informed 
consent form), rather than collect all protocol-
related AEs, only protocol-related SAEs will be 
collected 
To ensure reporting of AEs during the screening 
period is focused on significant events 
Section 7.8.1.4 
Investigator assessment of causality is added to 
the information required in the initial SAE 
report 
If causality is not provided with the initial report, it is 
conservatively handled as a SUSAR until causality is 
obtained 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 93 of 97 
Confidential 
 
Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Section 7.8.1.5 
The following statement is removed: 
“Investigators are required to report all SAEs, 
including anticipated SAEs, to the sponsor (see 
Section 7.8.1.4).” 
Investigator reporting requirements are already 
covered in Section 7.8.1.4 
Section 7.8.7 
Appendix C 
Provided equation to calculate QTcF 
For the convenience of study sites 
Section 9.3, Table 13 
Clarified definition of enrolled analysis set  
To be consistent with CRF 
Section 9.3, Table 13 
Revised definition of Response Evaluable 
Analysis Set to include all subjects in the safety 
analysis set with measurable disease and at least 
1 evaluable post-baseline disease assessment 
(per RECIST 1.1) or who discontinued study 
treatment due to death or unequivocal clinical 
progression 
To clarify that the Response Evaluable Analysis Set 
includes subjects with measurable disease 
Title Page, Synopsis, 
Section 7.3 
Section 9.4.12 
Incorporated changes described in China-
specific amendment 1 (see summary below) 
To create a single protocol for all regions 
 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 94 of 97 
Confidential 
 
Summary of Changes in China-Specific Amendment 1 
Section(s) 
Change 
Rationale 
Title Page 
Updated the Medical Monitor to reflect the respective roles and 
responsibilities of Zymeworks Inc. and BeiGene, Ltd in China. 
Administrative change. 
Synopsis, Section 7.3 and 
9.4.13  
Included a requirement for extensive PK in the first 10 subjects 
enrolled in China. Updated IDMC schedule to include additional 
IDMC meetings for safety in these subjects. 
To confirm ZW25 dose in 
Chinese population  
 
Summary of Changes in Amendment 1 
Section(s) 
Change 
Rationale 
Title Page 
The Sponsor information has been updated to reflect the 
respective roles and responsibilities of Zymeworks Inc. and 
BeiGene, Ltd. 
Administrative change. 
Synopsis, Schedule of 
Assessments, and Sections 
2, 6.2 , 6.3.2.3, 6.3.4, 6.4, 
7.7, and 9.4.11  
The EORTC QLQ-C30 and QLQ-BIL21 QOL questionnaires have 
been removed. Disease-related pain will now be assessed using the 
BPI short form rather than the QLQ-BIL21 pain score. 
For patient convenience and to 
use a more sensitive 
instrument, the BPI, to 
measure disease-related pain. 
Synopsis and Sections 2 
and 9.4.5  
To change the timeframe over which opioid use will be analyzed. To align with use of the BPI to 
measure disease-related pain. 
Synopsis and 
Sections 3.1 and 7.8.2  
To specify that absolute decreases of ≥ 10 percentage points 
below baseline LVEF will be considered AESI. 
Clarification. 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 95 of 97 
Confidential 
 
Summary of Changes in Amendment 1 
Section(s) 
Change 
Rationale 
Section 5.2.2  
The text has been revised as follows: 
ZW25 will be administered by IV infusion given over 
approximately 120–150 minutes. If the first 2 doses are well 
tolerated by a given subject, the 
infusion duration for that subject may be decreased to 90 minutes. 
If the next 2 doses are well tolerated, the infusion duration may 
be decreased to 
60 minutes. However, the infusion rate should not exceed 250 
mL/hour. Refer to the Pharmacy Manual for specific details. 
ZW25 must not be administered as an IV push or bolus. ZW25 
should not be mixed with other medications. See Section 5.4 for 
guidelines for management of infusion reactions. 
To align with current instructions 
for ZW25 dosing. 
Section 5.2.2.1 
The following language has been added: 
Note that there must be a minimum of 12 days between doses. 
Cycles will not be skipped. If a cycle is delayed for any reason, 
once the subject resumes treatment the next dose delivered will 
be considered Day 1 of the cycle that was delayed. If the Day 15 
dose of a cycle is delayed by ≥12 days, then that dose will be 
considered skipped. The next dose delivered will be Day 1 of the 
subsequent cycle. 
Clarification. 
Section 6.3.1.1  
Text has been added to state that the Cycle 1 Day 1 physical 
exam does not need to be repeated if completed for screening 
within the previous 3 days. 
Clarification. 
 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 96 of 97 
Confidential 
 
Summary of Changes in 
Amendment 1 
Section(s) 
Change 
Rationale 
Section 7.8.1.2  
The text has been revised as follows: 
Diagnosis vs. Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out 
of individual symptoms. Grouping of symptoms into a diagnosis should 
only be done if each component sign and/or symptom is a medically 
confirmed component of a diagnosis as evidenced by standard medical 
textbooks. If any aspect of a sign or symptom does not fit into a classic 
pattern of the diagnosis, report the individual symptom as a separate AE. 
Important exceptions for this study are adverse reactions associated 
with the infusion of study drug. For infusion reactions, do not use the 
NCI-CTCAE terms of “cytokine release syndrome,” “acute infusion 
reaction,” or “allergic or hypersensitivity reaction.” Instead, record each 
sign or symptom as an individual AE. If multiple signs or symptoms 
occur with a given infusion-related event, each sign or symptom should 
be recorded separately with its level of severity. 
To correctly reflect the 
procedure for reporting 
IRRs as AEs. Similar to 
other AEs, IRRs should be 
reported as diagnoses and 
not individual symptoms. 
Section 9.4.6.4  
The text has been revised as follows: 
Disease control is defined as a best response of CR, PR non-CR/non-PD 
(for subjects who have only non-target lesions), or SD per RECIST 1.1. 
The proportion of subjects who achieve disease control and the 
corresponding exact binomial 95% CI will be calculated. 
For consistency with the 
eligibility criteria, which 
only allows enrollment of 
subjects with target 
lesions. 
Throughout protocol 
Minor clarifications/corrections 
To provide clarity and 
consistency. 
 
 
 


Jazz Pharmaceuticals Ireland, Limited  
 
08SEP2023 
ZWI-ZW25-203 
Amendment 3 
Page 97 of 97 
 
 
Confidential 
 
 
PROTOCOL APPROVAL SIGNATURE 
Protocol Title: 
A Phase 2b, open-label, single-arm study of zanidatamab (ZW25) 
monotherapy in subjects with advanced or metastatic HER2-amplified 
biliary tract cancers 
Protocol Number: 
ZWI-ZW25-203 
This study will be conducted in compliance with the clinical study protocol (and amendments), 
International Council for Harmonisation (ICH) guidelines for current Good Clinical Practice (GCP) and 
applicable regulatory requirements. 
Sponsor Signatory 
 MD, PhD 
Sr. Medical Director 
Jazz Pharmaceuticals, Inc. 
See Document Approval page  
for eSignature and date of approval 
 


Signature Page for ZW25-203-03 Protocol Amendment
VV-CLIN-019723
Signature Page for ZW25-203-03 Protocol Amendment
VV-CLIN-019723
Approval Task - Approval of Document
Signing Verdict/Reason: I Approved This Document
Clinical
13-Sep-2023 20:53:16 GMT+0000

SAP_001.pdf: 
 
 
 
 
 
Statistical Analysis Plan 
Protocol Title: 
A Phase 2b, open-label, single-arm study of zanidatamab (ZW25) 
monotherapy in subjects with advanced or metastatic HER2-
amplified biliary tract cancers 
Protocol Number: 
ZWI-ZW25-203 
EudraCT Number: 
2020-000459-11 
Phase: 
2b 
Investigational Product: 
Zanidatamab or ZW25  
US IND Number: 
 
Sponsor (Rest of World): 
Zymeworks Inc. 
114 East 4th Avenue, Suite 800 
Vancouver, BC, Canada 
V5T 1G4 
 
 
Sponsor (China and South 
Korea): 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
2955 Campus Drive, Suite 200 
San Mateo, CA 94403  
USA 
 
BeiGene (Beijing) Co., Ltd, 
Room 101, 201, 402, 502, 
Building 1, No. 30 Science Park 
Road, Changping District, 
102206, Beijing, China 
 
 
 
 
 
 
 
 
 
 
 
 
Version - Date: 
Version 2.0 – 28-October-2022 
Author: 
 
 
 
 
 


Approval
Zymeworks:
BeiGene:


                       
                       


 
 
4 
 
1 
TABLE OF CONTENTS 
 
1 
TABLE OF CONTENTS ..................................................................................................4 
2 
LIST OF FIGURES ...........................................................................................................5 
3 
LIST OF TABLES ............................................................................................................5 
4 
LIST OF ABBREVIATIONS ...........................................................................................6 
5 
INTRODUCTION .............................................................................................................8 
6 
STUDY DESIGN ..............................................................................................................8 
6.1 
Description ..............................................................................................................8 
6.2 
Study Objectives and Endpoints .............................................................................9 
6.3 
Treatment Assignment and Blinding ....................................................................12 
6.4 
Statistical Hypotheses ...........................................................................................12 
6.5 
Determination of Sample Size ..............................................................................12 
6.6 
Timing of Analyses and Interim Analyses ...........................................................14 
7 
STATISTICAL CONSIDERATIONS ............................................................................14 
7.1 
Analysis Sets .........................................................................................................14 
7.2 
Subgroups .............................................................................................................15 
7.3 
Handling of Missing Data .....................................................................................16 
7.4 
Multicenter Studies ...............................................................................................18 
7.5 
Adjustments for Covariates ..................................................................................18 
7.6 
Multiple Comparisons, Multiplicity, and Multiple Testing ..................................18 
7.7 
Data Conventions, Definitions, and Formulas ......................................................19 
8 
STATISTICAL METHODOLOGY ................................................................................20 
8.1 
Trial Details ..........................................................................................................20 
8.2 
Analysis of Efficacy .............................................................................................24 
8.3 
Analysis of Safety .................................................................................................29 
8.4 
Quality of Life, Disease-Related Pain Analyses and Opioid Use ........................36 
8.5 
Immunogenicity Analyses ....................................................................................38 
8.6 
Pharmacokinetic Analyses ....................................................................................38 
8.7 
Biomarker Analyses ..............................................................................................41 
8.8 
Exploratory Analyses ............................................................................................41 
8.9 
Subgroup Analysis of Subjects Enrolled from China sites ...................................41 
9 
CHANGES IN THE PLANNED ANALYSIS ................................................................43 
10 
REFERENCES ................................................................................................................44 
 


 
 
5 
 
2 
LIST OF FIGURES 
Figure 1: Study Design ................................................................................................................. 9 
 
3 
LIST OF TABLES 
Table 1: Clopper-Pearson 95% Confidence Intervals for N=75 Subjects ............................. 12 
Table 2: Clopper-Pearson 95% Confidence Intervals for N=25 Subjects ............................. 13 
Table 3:  Probabilities of Detecting ≥1 Adverse Events .......................................................... 13 
Table 4: Analysis Sets ................................................................................................................. 14 
Table 5: Determination of Confirmed Best Overall Response ............................................... 25 
Table 6: Censoring and Event Scheme for PFS ....................................................................... 26 
Table 7: Censoring and Event Scheme for OS ......................................................................... 29 
Table 9: Toxicity Terms for Laboratory Parameters Graded for both High and Low values
....................................................................................................................................................... 34 
Table 10: PK Sampling time points for Zanidatamab ............................................................ 38 
Table 11: Steady-State Extensive Pharmacokinetic Sampling Schedule on Cycle 4 or any 
Subsequent Cycle ........................................................................................................................ 39 
Table 12: Analysis Sets for Efficacy Analysis for Subjects Enrolled from China sites ........ 42 
 
 
 


 
 
6 
 
4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
λz 
terminal elimination rate constant 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the serum concentration-time curve from zero to infinity 
AUC0-t 
area under the serum concentration-time curve from zero to the last measurable 
concentration 
AUCtau 
area under the serum concentration-time curve from zero to the end of dosing interval 
BOR 
best overall response 
BTC 
biliary tract cancer 
Cave 
average concentration 
CC 
cholangiocarcinoma 
CDE 
Center for Drug Evaluation (China) 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
Cmin 
minimum concentration 
COVID-19 
Coronavirus Disease 2019 
CR 
complete response 
CRF 
case report form 
CSS 
steady state concentration 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
DCR 
disease control rate 
DOR 
duration of response 
ECC 
extrahepatic cholangiocarcinoma 
ECD 
extracellular domain 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
EQ-5D 
European Quality of Life 5-Dimensions questionnaire 
FDA 
Food and Drug Administration 
HER2 
human epidermal growth factor receptor 2 
ICC 
intrahepatic cholangiocarcinoma 
ICH 
International Council for Harmonisation  
ICR 
independent central review 
IDMC 
independent data monitoring committee 
IHC 
immunohistochemistry 
IND 
investigational new drug 
ISH 
in situ hybridization 
LVEF 
left ventricular ejection fraction 


 
 
7 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition scan 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NMPA 
National Medical Products Administration 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PRO 
patient-reported outcome 
PS 
performance status 
QxW 
every ‘x’ weeks 
QOL 
quality of life 
QTcF 
Corrected QT interval using Fridericia formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SMQ 
Standardised MedDRA Query 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
t1/2 
half-life  
tmax 
time to maximum concentration  
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 


 
 
8 
 
5 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical methods, assumptions, and details of 
the planned statistical analyses to be performed for Study ZW25-203.  
6 
STUDY DESIGN 
6.1 
Description 
This pivotal, multicenter, open-label, single-arm trial will evaluate the anti-tumor activity of 
zanidatamab monotherapy in subjects with HER2-amplified, inoperable and advanced or 
metastatic biliary tract cancer (BTC), including intrahepatic cholangiocarcinoma (ICC), 
extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC). Subjects must have 
received at least 1 prior gemcitabine-containing systemic chemotherapy regimen for advanced 
disease, and experienced disease progression after or developed intolerance to the most recent 
prior therapy. New or archival tumor tissue is required from all subjects for HER2 amplification 
and HER2 protein expression testing at a central lab using in situ hybridization (ISH) and 
immunohistochemistry (IHC) assays. Subjects may be tested for HER2 status at the central lab 
any time after diagnosis of advanced or metastatic disease and before study enrollment. Subjects 
who elect to be pre-screened for HER2 status must sign a separate informed consent for 
collection, storage, and analysis of the tumor tissue. Once a prospective subject experiences 
disease progression or develops intolerance to his/her most recent prior therapy, the main consent 
for the remaining screening assessments must be signed. 
Two cohorts of subjects will be enrolled: 
x Cohort 1, comprising subjects with HER2 amplification by ISH and HER2 
overexpression by IHC, i.e., IHC 2+ or 3+ 
x Cohort 2, comprising subjects with HER2 amplification by ISH and HER2 IHC 0 or 1+ 
Enrolled subjects will receive zanidatamab, 20 mg/kg given intravenously (IV) every 2 weeks 
(Q2W) until 1 of the protocol-defined treatment discontinuation criteria are met. The primary 
endpoint of confirmed objective response rate (ORR) per the Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST 1.1) will be evaluated by independent central review (ICR). 
Disease response will be evaluated every 8 weeks (Q8W) with a ± 7-day window, using 
computed tomography (CT) or magnetic resonance imaging (MRI) scans.   
Subjects who discontinue treatment with zanidatamab for any reason should enter the 30-day 
follow-up period, as well as survival follow-up. The study schema is presented in Figure 1. 
 


9
Figure 1: Study Design
CT = computed tomography; EOT = end of treatment; IV = intravenous; MRI =magnetic resonance imaging; 
ZW25 = zanidatamab
* Timed from Cycle 1 Day 1.
** Subjects may be tested for HER2 status any time after diagnosis of advanced or metastatic disease and 
before study enrollment. Subjects who elect to be pre-screened for HER2 status must sign a separate informed 
consent for collection, storage, and analysis of the tumor tissue.
*** Every 8 weeks until disease progression or start of subsequent anticancer therapy.
**** Every 3 months until death, lost to follow-up, withdrawal of consent, study completion, or study termination 
by sponsor.
6.2
Study Objectives and Endpoints
Objectives
Endpoints
Primary: 
●To evaluate the anti-tumor activity of zanidatamab 
monotherapy in subjects with advanced or 
metastatic HER2-amplified biliary tract cancers 
(BTC) 
●Confirmed objective response rate (ORR) by the 
Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1), assessed by 
independent central review (ICR)
Efficacy 
follow-
up: 
Every 
8 weeks
***


 
 
10 
 
Objectives 
Endpoints 
Secondary: 
● To further evaluate the anti-tumor activity of 
zanidatamab monotherapy in subjects with 
advanced or metastatic HER2-amplified BTC 
 
● Duration of response (DOR) by RECIST 1.1 
assessed by ICR. 
● Proportion of subjects with a DOR ≥16 weeks by 
RECIST 1.1 assessed by ICR.  
● Disease control rate (DCR) by RECIST 1.1 
assessed by ICR. 
● Progression-free survival (PFS) by RECIST 1.1 
assessed by ICR. 
● ORR by RECIST 1.1 assessed by investigator. 
● DOR by RECIST 1.1 assessed by investigator. 
● Proportion of subjects with a DOR ≥16 weeks by 
RECIST 1.1 assessed by investigator.  
● DCR by RECIST 1.1 assessed by investigator. 
● PFS by RECIST 1.1 assessed by investigator. 
● Overall survival (OS) 
 
● To evaluate the safety and tolerability of 
zanidatamab monotherapy in subjects with 
advanced or metastatic HER2-amplified BTC 
● Frequency and severity of adverse events (AEs) 
● Frequency of serious adverse events (SAEs) and 
deaths 
● Frequency and severity of clinical laboratory 
abnormalities 
● Frequency of dose modifications of zanidatamab 


 
 
11 
 
Objectives 
Endpoints 
● To evaluate the pharmacokinetics (PK) of 
zanidatamab 
● Serum concentrations of zanidatamab as a function 
of time post-dosing 
● PK parameters for single (first) dose and multiple 
doses 
● Population pharmacokinetics and exposure-
response analyses. To be conducted according to 
the data analysis plan entitled “Population 
Pharmacokinetic and Exposure-Response Analysis 
to Support Regulatory Biologics License 
Application Submission of Study 
ZWI- ZW25- 203 in Biliary Tract Cancer” 
● To evaluate the immunogenicity of zanidatamab 
● Frequency, duration, and time of onset of anti-drug 
antibodies (ADA) and neutralizing antibodies, if 
applicable 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
CCI


 
 
12 
 
6.3 
Treatment Assignment and Blinding 
This is a single-arm study that will enroll subjects into 2 separate cohorts, based on their HER2 
status. Prior to the primary analysis for the study, access to the ICR response assessment data 
will be limited only to a small team as defined in the Data Access Plan for data cleaning 
purposes to limit potential bias. 
6.4 
Statistical Hypotheses 
This is a single-arm, open-label study. No statistical hypotheses will be tested. 
6.5 
Determination of Sample Size 
This study will enroll approximately 100 subjects: approximately 75 subjects in Cohort 1 and 
approximately 25 subjects in Cohort 2. No formal sample size calculations were performed.  
Approximately 75 subjects will be enrolled in Cohort 1 to evaluate the primary endpoint of 
confirmed ORR for the primary analysis of efficacy. The 2-sided, exact Clopper Pearson 
binomial 95% confidence intervals (CIs) that could be observed with this sample size are listed 
in Table 1. A minimum of 23 subjects with confirmed objective response from a sample-size of 
75 would result in the lower bound of a two-sided, exact Clopper Pearson binomial 95% CI 
exceeding 20 percentage points.  
Table 1: Clopper-Pearson 95% Confidence Intervals for N=75 Subjects 
Confirmed ORR  
95% CI 
Percent 
Responses 
Lower 
Upper 
20.0% 
15 
11.7% 
30.8% 
25.3% 
19 
16.0% 
36.7% 
30.7% 
23 
20.5% 
42.4% 
36.0% 
27 
25.2% 
47.9% 
40.0% 
30 
28.9% 
52.0% 
45.3% 
34 
33.8% 
57.3% 
50.7% 
38 
38.9% 
62.4% 
 
Approximately 25 subjects will be enrolled in Cohort 2 to evaluate the primary endpoint of 
confirmed ORR as a secondary analysis of efficacy. The 2-sided, exact Clopper-Pearson 
binomial 95% CIs that could be observed with a sample size of 25 subjects are listed in Table 2.   


 
 
13 
 
Table 2: Clopper-Pearson 95% Confidence Intervals for N=25 Subjects 
Confirmed ORR  
95% CI 
Percent 
Responses 
Lower 
Upper 
20.0% 
5 
6.8% 
40.7% 
24.0% 
6 
9.4% 
45.1% 
28.0% 
7 
12.1% 
49.4% 
32.0% 
8 
15.0% 
53.5% 
36.0% 
9 
18.0% 
57.5% 
40.0% 
10 
21.1% 
61.3% 
44.0% 
11 
24.4% 
65.1% 
48.0% 
12 
27.8% 
68.7% 
With a sample size of 100 subjects (Cohorts 1 and 2 combined), the probabilities of detecting 
1 or more treatment-emergent adverse events (TEAEs) for various frequencies of occurrence in 
this population are listed in Table 3. 
Table 3:  Probabilities of Detecting ≥1 Adverse Events 
Frequency of  
Adverse Event 
Binomial 
Probability 
0.1% 
10% 
1% 
63% 
5% 
99% 
 
 
 


 
 
14 
 
6.6 
Timing of Analyses and Interim Analyses 
No interim analyses of the efficacy will be performed for this study. The primary analysis of 
efficacy will be performed approximately 6 months after the last subject has been enrolled into 
Cohort 1. 
 
Safety and study conduct will be monitored throughout the study by an independent data 
monitoring committee (IDMC). The committee is tasked with monitoring the safety of 
participants in this study through regular and/or ad hoc meetings. The first IDMC meeting will 
be held after the first 25 subjects have received at least 1 dose of study treatment; subsequent 
meetings will be held quarterly to review cumulative safety data to identify any potential new 
safety signals. Additional IDMC meetings will be held at least 28 days after the tenth subject 
enrolled in China has received 1 dose of zanidatamab to review safety. The IDMC will be 
responsible for making recommendations to the sponsor as to appropriate study direction; further 
details will be provided in the IDMC charter. 
7 
STATISTICAL CONSIDERATIONS 
7.1 
Analysis Sets 
For the purposes of analysis, the subject analysis sets are defined in Table 4.  
Table 4: Analysis Sets 
Analysis Set  
Description  
Screened 
All participants who sign the main study informed consent 
Enrolled 
All participants who sign the main study informed consent, were eligible for the 
study, and received approval to enroll at the end of Screening.  
Safety 
All safety evaluable subjects enrolled in Cohorts 1 and 2. 
A subject is considered safety evaluable if they received any amount of zanidatamab. 
Efficacy 
The following Efficacy Analysis Sets will be evaluated for this study:  
x 
Cohort 1 (Primary) - Includes all safety evaluable subjects enrolled in 
Cohort 1. The primary analysis of efficacy will be performed using this 
analysis set. 
x 
Cohort 2 - Includes all safety evaluable subjects enrolled in Cohort 2. 
Response Evaluable 
The following Response Evaluable Analysis Sets will be evaluated for this study:  
x 
Cohort 1 - Includes all response evaluable subjects enrolled in Cohort 1 
x 
Cohort 2 - Includes all response evaluable subjects enrolled in Cohort 2 
Response Evaluable includes all subjects in the safety analysis set with measurable 
disease at baseline and at least 1 evaluable post-baseline disease assessment (per 
RECIST 1.1) or who discontinued study treatment due to death or unequivocal 
clinical progression. 
Pharmacokinetics 
All subjects who received any amount of zanidatamab and have at least 1 post-
baseline PK assessment. 


 
 
15 
 
Immunogenicity 
All subjects who received any amount of zanidatamab and have both baseline ADA 
and at least 1 post-baseline ADA results available 
 
7.2 
Subgroups 
The following subgroups may be evaluated for efficacy. Subgroups with 5 or fewer subjects may 
not be evaluated.  
x Disease subtype 
- Gallbladder cancer (GBC) 
- Intrahepatic cholangiocarcinoma (ICC) 
- Extrahepatic cholangiocarcinoma (ECC) 
x . Intolerance to the most recent prior therapy 
- Yes  
- No (progressed on the most recent regimen) 
x Number of prior regimens for treatment of metastatic disease 
- Less than 2 regimens 
- 2 or more regimens 
x HER2 expression 
Cohort 1 
 IHC3+  
 IHC2+ 
 IHC Result Not available 
Cohort 2 
 IHC1+  
 IHC0 
x Geographic region 
- North America (Canada, US) 
- Asia (China, South Korea) 
- Other (Chile, France, Italy, Spain, UK) 
x Sex (Female, Male) 
x Age 
- <65 years  
- ≥65 years 
- <75 years 
- ≥ 75 years 
x Baseline ECOG 
- ECOG = 0 
- ECOG = 1  


 
 
16 
 
x Disease stage at baseline (study entry) 
- Stage IIb and Stage III 
- Stage IV 
x Race 
- Asian 
- Non-Asian 
7.3 
Handling of Missing Data 
7.3.1 
Cohort Assignment 
Subjects with missing or indeterminate IHC results will be assigned to Cohort 1. The number and 
proportion of subjects with missing IHC results will be presented. 
7.3.2 
Efficacy Data 
Partial or Missing Dates  
Partial or missing death dates, tumor assessment dates, dates of last contact, dates of onset of 
post-study treatment anti-cancer therapy, and dates used in computing secondary efficacy 
endpoints will be imputed as follows: 
x Missing day only: For partial dates with only the day of the month missing, the day 
will be imputed as the 15th day of the month, provided that a preceding date of 
interest does not occur on/after the 15th day of the month. If the preceding date does 
occur on/after the 15th day in the same month, then the missing day will be imputed 
as half the distance between the preceding date and the end of the month. 
x Missing month and day: For partial dates with the month and day missing, the month 
and day will be imputed as July 1st, provided that a preceding date of interest does not 
occur in the same year. If the preceding date occurs in the same year, then the month 
and day will be imputed as half the distance from the preceding date to the end of the 
known year. 
x Missing month, day, and year: Where appropriate, specific rules for handling 
completely missing dates are described in the applicable endpoint and analysis 
section. 
In situations where the above rules result in an illogical time (e.g., negative study day, negative 
cycle day, etc.) the date will be imputed as EOT date + 1 day. 


 
 
17 
 
Missing Post-Baseline Assessments 
For RECIST based endpoints, subjects without any post-baseline tumor assessments will be 
handled as follows: 
x For the analysis of PFS, subjects will be handled as described in Table 6. 
x Subjects with no evaluable post-baseline response assessments will be considered as 
Not Evaluable (NE) for best overall response.  
7.3.3 
Quality of Life Data 
There will be no imputation of missing data for either the EQ-5D or BPI. 
7.3.4 
Safety Data 
7.3.4.1 Adverse Event Start Dates 
For AEs where the date of onset is during or after administration of the first dose of study 
treatment, missing or partial start dates will be imputed as the earliest possible date that is on or 
after the date of the first dose of study treatment (zanidatamab). For events indicated on the CRF 
as occurring prior to first dose of study treatment, missing or partial dates will not be imputed.  
x Missing day only: If the start date and date of first dose share the same month and year, 
the missing start day will be imputed as the day of first dose. If the start date month is 
after the month of first dose, day will be imputed as the 1st (i.e., 01-MMM-YY). 
x Missing month and day: If the start date and date of first dose share the same year, day 
and month will be imputed as the day and month of first dose. If the start date year is 
after the year of first dose, the month and day will be imputed as January 1st (i.e., 01-
JAN-YY). 
x Missing month, day, and year: Missing start dates will be imputed as the date of first 
dose.  
7.3.4.2 Adverse Event End Dates 
Missing or partially missing end dates for AE which are known to have resolved will be imputed 
as follows: 
x Missing day only: The day will be imputed as last day of the month (e.g., 31-MMM-YY or 
30-MMM-YY). The AE end date is then imputed as the minimum of {last day of the month} 
and {death date}. If the month and year are the same as the data cutoff date month and year, 
then the data cutoff date will be used as the imputed AE end date.  


 
 
18 
 
x Missing month and day: The missing month and missing day will be imputed as December 
31. The AE end date is then imputed as the minimum of {Dec 31 of the year}, {death date}, 
{End of Study date} and {data cutoff date}.   
x Missing month, day, and year: The AE end date will be imputed as the minimum of {death 
date}, {End of Study date} and {data cutoff date}. 
7.3.5 
Pharmacokinetic Data 
Missing values for PK measurements will be listed as missing and excluded from the calculation 
of summary statistics. If a PK result is available but the collection time is missing or incomplete, 
then the nominal collection time indicated in the case report form (CRF) will be used. Sample 
concentrations that are below the lower limit of quantification (LLOQ) will be shown as less 
than reportable (<LLOQ) in the individual subject listings and imputed as follows for the 
purposes of calculating summary statistics and producing graphical summaries: 
x If the sample was collected prior to the 1st dose of zanidatamab, then the value will be 
imputed as zero. 
x If the sample was collected after the 1st dose of zanidatamab, then the value will be 
imputed as the LLOQ.  
Exclusion of PK data will be based on documented errors in dosing, sample labeling, sample 
handling, or bioanalysis. Excluded data will not be used in calculations for any tabulated or 
graphical summaries. Subjects that were not dosed or were not dosed in accordance with their 
assigned dose level, will be excluded from any tabulated or graphical summaries. Biologically 
implausible data may also be excluded in the summaries; however, all individual data will be 
listed and any exclusion, along with the corresponding rationale, will be noted. 
7.4 
Multicenter Studies 
The primary set of analyses will be conducted using pooled data from all sites. There are 
multiple sites in this study, however it is not anticipated that any center will accrue enough 
subjects to warrant an analysis by center.  
7.5 
Adjustments for Covariates 
No adjustments for covariates will be performed. 
7.6 
Multiple Comparisons, Multiplicity, and Multiple Testing 
No adjustments for multiple comparisons will be performed.  


 
 
19 
 
7.7 
Data Conventions, Definitions, and Formulas 
The following data conventions will be used for the tables, listings, and figures. 
x Study drug: Zanidatamab or ZW25 
x Baseline value of a study assessment: The last non-missing observation prior to the first 
dose of zanidatamab, unless otherwise specified. If both a planned assessment and repeat 
assessment (e.g., retest) meet the above criteria and were collected on the same date and 
time, the repeat assessment will be used as baseline. 
x Study day of a study event or assessment: The difference between the date of the event 
or assessment and the date of first dose plus 1 for events or assessments occurring on or 
after the day of first dose. For example, if an event occurs on 08JUN2014 and the date of 
first dose was 06JUN2014, the study day of the event is 3. For events or assessments 
occurring before the day of first dose, it will be the difference between the date of the 
event or assessment and the date of first dose. For example, if an event occurs on 
05JUN2014 and the date of first dose was 06JUN2014, the study day of the event is -1, 
which is consistent with the Study Data Tabulation Model (Version 3.2) from Clinical 
Data Interchange Standards Consortium (CDISC). 
x Pre-treatment Period: Period of time prior to first dose of zanidatamab  
x Study Treatment Period: Period of time that begins on the date of the first dose of 
zanidatamab through 30 days after the date of the final dose of zanidatamab. 
x Post-treatment Follow up Period: Period of time that begins 1 day after EOT and ends 
at End of Study (EOS).  
x Disease Assessment dates: In the event, radiographic assessment for a subject occurs 
over multiple days for a visit, the following convention will be used to determine the date 
of the RECIST disease response assessment: 
- For a response of Progressive Disease (PD), the date of the earliest radiographic 
scan will be used. 
- For responses other than PD, the date of the latest radiographic scan will be used. 
x Duration of zanidatamab Treatment:  
Duration of zanidatamab treatment is defined as the difference in days between date of 
first dose and the earliest of the following dates: 
- Date of last dose + 14 days 
- Date of death  
- Date of subsequent anticancer therapy 
Duration (days) = (Earliest date above) – (date of first dose) + 1. 


 
 
20 
 
x Total Cumulative Dose:  
Total cumulative dose (mg) = sum of all doses (mg) received during the entire treatment 
period duration.  
x Actual Dose Intensity (ADI): 
ADI is the actual dose (mg/kg) per week that the subject received over the entire 
treatment period. For calculating ADI, the treatment period is defined as time from 
the first dose of study drug to date of last dose + 14 days, regardless of death status 
during this period.  
x Intended Dose Intensity (IDI): 
IDI is the intended dose of drug (mg/kg) per week 
x Relative Dose Intensity (RDI):  
RDI is the percent of the intended dose intensity over the entire treatment period: 
ܴܦܫ= ܣܦܫ× 100
ܫܦܫ
 
8 
STATISTICAL METHODOLOGY 
8.1 
Trial Details 
The following information will be summarized for the safety analysis set unless otherwise 
specified.  
8.1.1 
Enrollment 
The following study enrollment information will be summarized, for all screened subjects.  
x Number of subjects treated and the percentage Number of screen failures and the 
percentage Number and percentage of subjects enrolled and treated in each region and 
country. 
x Screen failures 
- Demographic variables: age, gender, race, country, and ethnicity. 
- Number and percentage of subjects who failed screening by reason. 
- Number and percentage by region and country  
x A listing of subjects who failed screening will also be produced, with reasons for screen 
failure and available demographic information. 


 
 
21 
 
In addition, the following summaries will be provided for treated subjects. 
x Number and percentage of subjects enrolled and treated in each cohort. 
x . 
8.1.2 
Subject Disposition  
The following disposition information will be summarized. 
x Number and percentage of subjects who discontinued zanidatamab and the associated 
reasons for discontinuation. 
x Number and percentage of subjects who discontinued study and the associated 
reasons for discontinuation from the study 
x Number and percentage of subjects actively in post-treatment (survival) follow-up.  
x Number of subjects in each analysis set 
x Duration of study follow-up, defined as the time from first dose to the data cut off 
date. 
8.1.3 
Protocol Deviations 
Protocol deviations (as defined in the ZWI-ZW25-203 Monitoring Plan) will be identified by site 
monitors, the medical monitor and by checks of the clinical database. Protocol deviations will be 
classified into prespecified sub-types and categorized as either important deviations or non-
important deviations. Important deviations are deviations that are considered significant.  
Important deviations will be summarized for each cohort. Per the study’s COVID-19 deviation 
guideline, all deviations due to COVID-19 are documented on source documents and tracked in 
EDC. The frequencies of missed tumor scans and missed infusions due to COVID-19 will 
provided.   
8.1.4 
Baseline Characteristics and Disease History 
Baseline characteristics will be summarized using counts and percentages for categorical 
variables and summary statistics (mean, quartiles, standard deviation, and range) for continuous 
variables. Categorical variables listed in this section that are also identified as efficacy subgroups 
of interest (Section 7.2) will be summarized using the categories defined in that section. 
Characteristics to be summarized include the following: 
x Demographic variables: age, sex, race and ethnicity (Hispanic, Non-Hispanic) 
x Physical characteristics: height (cm), weight (kg)  
x ECOG performance status 


 
 
22 
 
x Region or Country 
x Disease history:  
- Primary disease (disease subtype) 
 Gallbladder cancer (GBC) 
 Intrahepatic cholangiocarcinoma (ICC) 
 Extrahepatic cholangiocarcinoma (ECC) 
- Stage at initial diagnosis (Stage I, II, …IV and including substages e.g., IIb) 
- Duration (months) from initial diagnosis to metastatic/locally advanced 
- History of brain metastases (Yes, No) 
- Number of years since brain metastases was diagnosed 
- Tumor classification/characteristics 
 HER2 IHC tumor expression score (0, 1+, 2+, 3+, No result) 
- Investigator assessed tumor characteristics per RECIST 1.1.  
 Sum of diameters for target lesions (mm) 
- ICR assessed tumor characteristics per RECIST 1.1.   
 Measurable disease status (Yes, No) 
 Sum of diameters for target lesions (mm) 
- Prior radiotherapy 
 Any (Yes, No) 
 Total number of treatments 
- Prior cancer surgery 
 Any (Yes, No) 
 Total number of surgeries 
- Prior systemic anticancer therapy  
 Any (Yes, No) 
 Total number of regimens 
 Received Gemcitabine+Cisplatin 
- Prior systemic anticancer therapy for metastatic/locally advanced disease 
 Any (Yes, No) 


 
 
23 
 
 Number of regimens received 
 Number of regimens received (<2, 2+)  
 Received Gemcitabine 
 Prior exposure to:  
x PD1 / PDL1 inhibitor  
x Gemcitabine monotherapy 
x Gemcitabine and Oxaliplatin in combination 
x Gemcitabine and Cisplatin in combination 
x Gemcitabine and Fluoropyrimidine in combination 
x Gemcitabine and other combination therapies 
x Fluoropyrimidine based therapies (without Gemcitabine) 
- Baseline hepatic impairment (Per the National Cancer Institute Organ 
Dysfunction Working Group) 
 None  
 Mild 
 Moderate  
 Severe 
- Baseline renal impairment (Per the Cockcroft-Gault formula for estimating 
creatinine clearance and FDA guidance titled: Pharmacokinetics in Patients with 
Impaired Renal Function - Study Design, Data Analysis, and Impact on Dosing 
and Labeling [September 2020]) 
 Mild to moderate  
 Normal 
8.1.5 
Prior Systemic Anticancer Therapy, Radiotherapy and Surgeries 
Prior systemic anticancer therapies will be coded using the World Health Organization Drug 
Dictionary (WHO-DD) Version 2009Q3 or higher and listed by ATC level 4 code. Prior surgery 
and radiotherapies will also be listed.  
8.1.6 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) and listed and summarized by preferred term using counts and percentages. Multiple 
occurrences of the same medication within a subject will be summarized only once.  


 
 
24 
 
8.1.7 
Concomitant Procedures 
Concomitant procedures will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 24.0 or higher and listed and summarized by procedure and indication using 
counts and percentages. Multiple occurrences of the same procedure within a subject will be 
summarized only once. 
 
8.2 
Analysis of Efficacy 
The primary efficacy analysis will be based on the Cohort 1 Efficacy Analysis Set. In addition, a 
pooled analysis combining Cohorts 1 and 2 may be presented. Additional analyses will be 
conducted on the Response Evaluable Analysis sets as described in Table 4. 
8.2.1 
Best Overall Response 
Best overall response (BOR) is defined as the best response observed per RECIST 1.1 from start 
of the study treatment until any of the following occurring for a subject: 
x Receipt of non-protocol specified anticancer therapy 
x Documented disease progression 
x Death from any cause 
x Subject withdrawal of consent 
Confirmed BOR requires confirmation of CR or PR by a subsequent tumor assessment that is 
performed a minimum of 4 weeks from when the initial response is observed. See Table 5 for 
more details. 
BOR and confirmed BOR will be summarized using counts and percentages for both the ICR 
and investigator assessments. Confirmed best overall response will be determined as illustrated 
in Table 5. Subjects who die and have no post baseline radiographic scans will be categorized as 
not evaluable (NE) for BOR and confirmed BOR (Section 7.3.2). 
Concordance and discordance of ICR and investigator assessment of confirmed BOR will be 
summarized using counts and percentages.  
 


 
 
25 
 
Table 5: Determination of Confirmed Best Overall Response  
First Time Point Response 
Second Time Point 
Response 
Confirmed Response 
(Best Response) * 
PD 
No further evaluation 
PD 
NE 
PD 
PD 
CR 
PD 
SD or PD (1) 
PR 
PD 
SD or PD (1) 
SD 
PD 
SD or PD (1) 
CR 
CR 
CR 
CR 
NE ** 
SD or NE (2) 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD (3) ** 
SD 
PR 
NE ** 
SD or NE (2) 
SD 
CR 
SD 
SD 
PR 
SD 
SD 
SD 
SD 
SD 
NE 
SD or NE (2) 
NE 
CR 
SD 
NE 
PR 
SD 
NE 
SD 
SD 
NE 
NE 
NE 
* A Best Response of SD can only be made after the subject is on-study for a minimum of eight (8) weeks 
(56 days) ± fourteen (14) days. If the subject is not on-study for this amount of time, any tumor assessment 
indicating stable disease before eight (8) weeks (56 days) will have a Best Response of NE unless PD is 
identified. 
** Subsequent documentation of CR may provide confirmation of a previously identified CR for subjects 
where the second integrated response was NE. Subsequent documentation of PR may provide confirmation 
of a previously identified PR for subjects where the second integrated response was NE or SD. If the third 
TPR confirms the CR (or PR) then the Confirmed Response will be CR (or PR). For this study, only one (1) 
intervening NE is allowed between CRs/PRs. For example: 
CR NE CR = CR; PR NE PR = PR. Additionally, one (1) SD is allowed between PRs (e.g., PR SD PR = PR). 
For this study, one (1) intervening NEs are allowed between CRs/PRs but one (1) intervening SD is allowed 
only between PRs. For example, CR NE CR = CR; PR NE PR = PR; CR SD CR ≠ CR; PR SD PR = PR. 
Note: in the following scenario, PR SD NE PR, the second PR is not a confirmed PR. 
(1) Best response will be SD if the first TPR is after eight (8) weeks (56 days) ± fourteen (14) days on-study. 
Otherwise, the best response will be PD. 
(2) Best response will be SD if the first TPR is after eight (8) weeks (56 days) ± fourteen (14) days on-study. 
Otherwise, the best response will be NE. 
(3) TPR is SD if the increase from the first to the second assessment does not qualify for PD. 
Source Independent review charter, Version 1.0; Bioclinica: 03Aug2020 
8.2.2 
Objective Response and Confirmed Objective Response 
Objective response is defined as achieving a BOR of CR or PR per RECIST 1.1. The proportion 
of subjects with an objective response and the corresponding two-sided, exact Clopper Pearson 
binomial 95% CI will be calculated for both the ICR and investigator assessments of disease 
response. 
Confirmed objective response is defined as achieving a confirmed BOR of CR or PR per 
RECIST 1.1. The primary endpoint for this study is confirmed ORR based on the ICR response 
assessments. A secondary endpoint of confirmed ORR will also be computed based on the 
investigator response assessments. For each endpoint, the proportion of subjects with a 


 
 
26 
 
confirmed objective response and the corresponding two-sided, exact Clopper Pearson binomial 
95% CI using the Clopper-Pearson method (Clopper 1934) will be calculated. 
The time of first confirmed objective response is defined as the time from the first dose of study 
treatment to the earliest date a subject had a confirmed objective response (CR or PR).  This will 
be summarized for subjects who had a confirmed CR or PR as follows: 
x Descriptive statistics (n, mean, median, standard deviation, quartiles, range) of the 
time in weeks 
x Cumulative percentage responding by Week 9, Week 17, Week 25, Week 33, 
Week 41, and after Week 41 
Concordance and discordance of confirmed objective response per ICR and per investigator 
assessment will be summarized using counts and percentages.  
8.2.3 
Progression-Free Survival (PFS) 
PFS is defined as the time from the first dose of study treatment to the date of documented 
disease progression (per RECIST 1.1) or death from any cause, whichever occurs first. Subjects 
who are alive and have not progressed at the time of the analysis will be censored at the time of 
their last tumor assessment that was a CR, PR, SD, or non-CR/non-PD. Details of the censoring 
scheme for this endpoint are described in Table 6. 
Kaplan-Meier plots and estimates of the quartiles and their corresponding two-sided 95% CI will 
be computed using the Brookmeyer and Crowley method (Brookmeyer and Crowley 1982) with 
log-log transformation  (Collett 1994). The proportion of subjects with progression free survival 
at defined timepoints e.g., at 3, 6, 9 and 12 months will also be provided. Two-sided 95% CIs for 
these landmark PFS estimates will be based on the Greenwood estimator (Greenwood 1926). 
Table 6: Censoring and Event Scheme for PFS 
Scenario 
Progression/Censor Date 
Outcome 
No baseline or no post-baseline response 
assessments and no death  
Date of first dose 
Censored 
No disease progression (PD) 
Date of last CR, PR, SD, or non-CR/non-PD 
Censored 
New anti-cancer treatment started before 
first PD 
Date of last CR, PR, SD, or non-CR/non-PD 
on or prior to date of new anti-cancer 
treatment 
Censored 
Progressive disease (PD) 
 
Date of PD, if response assessment prior to 
PD was either CR, PR, SD, or non-CR/non-
PD  
Progressed 
 
 
Date of last CR, PR, SD, or non-CR/non-PD, 
if PD occurred after 2 or more consecutive 
missed and/or NE overall response 
assessments*   
Censored 
Death  
 
Death date, if last response assessment prior 
to death was CR, PR, SD, or non-CR/non-PD 
Progressed 
 


 
 
27 
 
and death occurred ≤18 weeks from the last 
response assessment 
Death date, if there are no baseline or no 
post-baseline response assessments and death 
occurred ≤18 weeks from the first dose. 
  
Progressed  
   
Date of last CR, PR, SD, or non-CR/non-PD, 
if death occurred after 2 or more consecutive 
missed and/or NE overall response 
assessments* 
Censored 
Date of first dose, if there are no baseline or 
no post-baseline response assessments and 
death occurred >18 weeks from the first dose   
Censored 
Note: * Two consecutive post-baseline tumor assessments refers to the next two protocol scheduled tumor 
assessments. Time is measured from the last adequate response assessment date. Subject will be considered 
to have missed two consecutive scheduled visits if no scans, scheduled or unscheduled, have occurred within 
the protocol-mandated disease assessment schedule; this will be within 2*(8 + 1) = 18 weeks. Note: The 
scanning schedule is every 8 weeks. 
 
Partial or missing dates of death dates, dates of last contact, and tumor assessment dates will be 
imputed as described in Section 7.3.2. Separate PFS analyses will be presented for the ICR and 
investigator tumor assessments. 
8.2.3.1 
PFS Sensitivity Analyses 
The following sensitivity analyses may be performed to assess the robustness of the estimates of 
PFS per ICR using the same statistical methods described in Section 8.2.3 for the analysis of 
PFS. 
x An analysis where clinical progression is treated as an event in addition to 
radiographic progression and death. Censoring rules per Table 6 and as stated in 
the below table will be followed.. 
Clinical progression 
 
Clinical progression date, if last response 
assessment prior to clinical progression is 
CR, PR, SD, or non-CR/non-PD and clinical 
progression occurred İ18 weeks from the 
last response assessment 
Progressed 
 
Clinical progression date if there are no post-
baseline, response assessments and clinical 
progression occurred İ18 weeks from the 
first dose.  
Progressed  
   
Date of last CR, PR, SD, or non-CR/non-PD, 
if clinical progression occurred after 2 or 
more consecutive missed and/or NE overall 
response assessments 
Censored 
Date of first dose, if there are no baseline or 
no post-baseline response assessments and 
Censored 


 
 
28 
 
clinical progression occurred >18 weeks 
from the first dose 
 
x An analysis in which subjects who initiate a new therapy prior to experiencing 
disease progression are considered to have had an event (PD) at the time of new 
therapy. 
x An analysis where subjects who die or progress after 2 or more consecutive 
missed or non-evaluable tumor assessments are considered to have had an event 
(PD) on the date of the first missed visit. 
8.2.4 
Disease Control Rate (DCR) 
Disease control is defined as a BOR of SD or confirmed CR or PR per RECIST 1.1. The 
proportion of subjects who achieve disease control and the corresponding two-sided, exact 
Clopper Pearson binomial 95% CI will be estimated for both the ICR and investigator 
assessments.  
8.2.5 
Clinical Benefit Rate 
Clinical benefit is defined as achieving SD for ≥ 24 weeks or a confirmed, BOR of CR or PR per 
RECIST 1.1. The proportion of subjects with clinical benefit and the corresponding two-sided, 
exact Clopper Pearson binomial 95% confidence interval will be calculated for both the ICR and 
investigator assessments. 
8.2.6 
Duration of Response 
DOR is defined as the time from the first confirmed objective response (CR or PR) to 
documented PD per RECIST 1.1 or death from any cause. Subjects who are alive and have not 
progressed at the time of the analysis will be censored at the time of their last tumor assessment 
that was a CR, PR, SD, or non-CR/non-PD. The same censoring rules outlined in Table 6 for 
PFS will be applied to DOR with date of first dose replaced by date of first response. DOR will 
be calculated based on the ICR response assessments and separately for the investigator response 
assessments. Only subjects who achieve a confirmed objective response will be included in the 
analysis of each endpoint. 
DOR will be analyzed using Kaplan-Meier methodology and a Kaplan-Meier plot of DOR will 
also be provided. Kaplan-Meier estimates of the quartiles (median, 25th and 75th) will be 
computed. Two-sided 95% CI for the quartiles using the Brookmeyer and Crowley method 
(Brookmeyer and Crowley 1982) with log-log transformation (Collett 1994) will be presented. 
Tumor assessment dates will be imputed as described in Section 7.3. In the event there are too 


 
 
29 
 
few confirmed responses to generate Kaplan-Meier estimates, DOR may be summarized 
descriptively (i.e., mean, median, standard deviation, minimum, and maximum). 
The proportion of subjects with a DOR t16 weeks and the corresponding two-sided, exact 
Clopper Pearson binomial 95% CI will also be calculated. In addition, the Kaplan-Meier 
probability and corresponding 2-sided 95% CI at Week 16 will be calculated.  
8.2.7 
Overall Survival (OS)  
Overall survival (OS) is defined as the time from the first dose of study treatment until the date 
of death from any cause or date last known alive for those who did not die.  
Specifically,  
OS = Date of death or date last known alive – Date of first dose + 1  
Subjects alive at the time of analysis will be considered as censored on the date the subject was 
last known to be alive (i.e., date of last contact). Subjects lacking data beyond the day of first 
dose will have their survival time censored on the date of first dose (i.e., OS duration of 1 day). 
Partial or missing dates of death dates and last known alive date will be imputed as described in 
Section 7.3.2. If resulting imputed death date is on or before last known alive date, then death of 
death will be set to last known alive date + 1 day. Details of the censoring scheme are described 
below in Table 7. 
 
Table 7: Censoring and Event Scheme for OS 
Scenario 
Progression/Censor Date 
Outcome 
Not known to have died by data cutoff date 
Date last known alive 
Censored 
Death 
Death date 
Death 
 
Completely imputed dates (e.g., the analysis cut-off date programmatically imputed to replace 
the missing end date of a dose administration record) will not be used to derive the last known 
alive date. 
Kaplan Meier estimates of the survival curve and quartiles will be calculated. The 2-sided 95% 
CIs for the quartiles will be calculated using the Brookmeyer and Crowley method (Brookmeyer 
and Crowley 1982) with log-log transformation (Collett 1994). Additionally, the probability of 
survival at timepoints from 3 months to the end of the follow-up period will be reported. 
8.3 
 Analysis of Safety  
All analyses of safety will be based on the safety analysis set which includes all safety evaluable 
Cohort 1 and 2 subjects.  


 
 
30 
 
8.3.1 
Extent of Exposure 
Zanidatamab exposure will be summarized using counts and percentages for categorical 
variables and summary statistics (mean, median, standard deviation, and range) for continuous 
variables. The following variables will be summarized.  
x Duration of exposure (see Section 7.7 for definition) 
x Number of treatment cycles initiated,  
x Total number of infusions received,  
x Relative dose intensity percent (see Section 7.7 for definition)  
x Total cumulative dose received (see Section 7.7 for definition)  
x Frequency of missed infusions and associated reasons  
x Frequency of dose reductions and associated reasons  
x Frequency of interrupted infusions and associated reasons  
x Frequency of delayed infusions and reasons  
8.3.2 
Adverse Events 
Definitions 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical study subject 
administered a medicinal product which does not necessarily have a causal relationship with this 
treatment. All AEs will be coded to standard “preferred terms” and system organ classifications 
(SOC) using MedDRA. Severity will be graded by study investigators using NCI-CTCAE v5.0. 
TreatmentEmergent Adverse Events (TEAEs) are defined as AEs with an onset during or after 
receipt of the first dose of zanidatamab and up to and including 30 days after the last dose. 
 
Summaries 
Adverse events will be summarized by preferred term (and SOC, or severity grade where 
appropriate). Multiple occurrences of the same AE within a subject will be summarized only 
once at the most severe grade level for the time frame under consideration. For summaries by 
severity, only the worst grade for an AE will be counted for a particular subject. AEs occurring 
prior to the first dose of zanidatamab or more than 30 days after the last dose of zanidatamab will 
be excluded from summaries but included in data listings. 
The following summaries will be produced: 
x Overall Summary of Adverse Events – Subject Incidence  


 
 
31 
 
x Overall Summary of Adverse Events – Event Frequency 
x Incidence of Treatment Emergent Adverse Events  
x Incidence of Grade 3 and Higher Treatment Emergent Adverse Events  
x Incidence of Zanidatamab Related Treatment Emergent Adverse Events  
x Incidence of Zanidatamab Related Grade 3 and Higher Treatment Emergent Adverse 
Events  
x Incidence of Treatment Emergent Adverse Events Leading to Discontinuation of 
zanidatamab  
x Incidence of Zanidatamab Related Treatment Emergent Adverse Events Leading to 
Discontinuation of Zanidatamab  
x Incidence of Treatment Emergent Adverse Events Leading to Dose Reduction 
x Incidence of Zanidatamab Related Treatment Emergent Adverse Events Leading to 
Dose Reduction 
x Incidence of TEAEs Leading to Dose Delay of Zanidatamab  
x Incidence of TEAEs Leading to Dose Interruption of Zanidatamab  
x Incidence of Grade 5 TEAE 
In addition to summary tables, the following listings will be produced. 
x All TEAEs 
x All non TEAEs 
x AEs Resulting in Death  
x AEs Leading to Discontinuation of Zanidatamab 
x AEs Leading to Dose Reduction of Zanidatamab 
x AEs Leading to Dose Delay of Zanidatamab  
x AEs Leading to Infusion Interruption   
8.3.3 
Serious Adverse Events and Deaths 
Serious adverse events (SAEs) will be summarized by preferred term and SOC using counts and 
percentages. Multiple occurrences of the same SAE within a subject will be counted only once 
for the timeframe under consideration. The following summaries of SAEs will be produced. 
x Incidence by decreasing frequency of preferred term 
x Incidence by SOC and decreasing frequency of SOC and preferred term 
x Incidence of zanidatamab related SAEs by decreasing frequency of preferred term 


 
 
32 
 
In addition to summary tables, listings of SAEs will be produced. 
The following summaries of death will be produced. 
x A table of death showing cause of death that occurred ≤ 30 days after last dose versus 
that occurred > 30 days after last doseA listing of all deaths  
8.3.4 
Adverse Events of Special Interest and Select Adverse Events 
AESIs to be summarized include the following: 
a. Infusion Related Reactions (IRR): Defined using the MedDRA preferred term of, 
“Infusion Related Reaction” or identified by the investigator as an infusion related 
reaction.  
b. Non-infectious Pulmonary toxicities: Defined as events in the Broad Interstitial Lung 
Disease SMQ. 
c. Potential Cardiac events: Defined as grade 2 or higher adverse events in the Broad 
Cardiac Failure SMQ or ECHO/MUGA scan results that indicate a post baseline decrease 
in LVEF of Ӌ 10 percentage points from pretreatment baseline and a value < 50%.  
d. Confirmed cardiac events: Defined as the subset of potential cardiac events (bullet c. 
above), that have been clinically reviewed by Zymeworks and determined to be 
consistent with cardiac events of absolute decrease in LVEF of Ӌ 10 percentage points 
from pretreatment baseline and a value < 50%, and/or grade Ӌ 2 heart failure. 
Select AEs to be summarized include the following: 
x Treatment-emergent diarrhea: Defined using the MedDRA preferred term of 
“Diarrhoea” 
x Treatment-emergent embryo-fetal toxicity: Defined using the modified Pregnancy and 
neonatal topics SMQ which excludes the sub SMQ Lactation related topics including 
neonatal exposure through breast milk (SMQ). 
Adverse events of special interest (AESIs) may be listed and summarized by MedDRA preferred 
term using counts and percentages. Multiple occurrences of the same AESI within a subject will 
be counted only once for the time frame under consideration. For summaries by severity, only 
the worst grade for an AESI will be counted for a particular subject. If 5 or fewer subjects have a 
particular AESI/Select AE, a data listing will be provided in lieu of a summary table.  
The time to first onset and duration will be calculated and summarized for each AESI and Select 
AE. For a particular AESI/Select AE, the time to first onset for a subject is defined as either: 
x Date of 1st occurrence – date of 1st infusion (C1D1) + 1 day 


 
 
33 
 
Or 
x Date and time of 1st occurrence – date and time of 1st infusion + 1 min 
The formula used above will depend on the unit of time used in the data collection for the event.  
Time to first onset will be summarized using summary statistics (n, mean, median, standard 
deviation, range). 
Time to resolution of AESI/Select AEs will be summarized for events that have an AE end date. 
Estimates of median, minimum and maximum time to resolution will be provided using 
descriptive statistics. Time to resolution is defined as the time from the start of the AE to the end 
date of the AE. The number and percentage of events without resolution will also be provided.  
a.  
8.3.4.1 
Characteristics of Infusion Related Reactions and Pulmonary 
Toxicities 
Symptoms associated with AESIs will be summarized using counts and percentages. Multiple 
occurrences of the same symptom within a subject will be summarized only once for the time 
frame under consideration.  
Additional summaries to characterize IRRs will include summary statistics of the time from the 
most recent zanidatamab exposure to the first subsequent IRR (for all infusions during which 
IRRs occur); percent of subjects with a history of any risk factor for IRRs including atopy, 
hypersensitivity, anaphylaxis, and/or allergy; the percent of subjects who underwent a tryptase 
test (and the proportion who had elevated tryptase levels); a frequency distribution of IRR onset 
by treatment cycle, and a frequency distribution of treatments (if any) provided for the IRRs. 
Additional summaries to characterize non-infectious pulmonary toxicities will include the 
proportion of subjects with symptoms; a frequency distribution of symptoms; the proportion of 
subjects with a history of risk factors for non-infectious pulmonary toxicity, and a frequency 
distribution of risk factors. 
8.3.4.2 
Characteristics Confirmed Cardiac Events  
Additional summaries to characterize confirmed cardiac events are data driven and may include 
summaries of the proportion of subjects with symptoms; the proportion of subjects with 
limitations to physical activity (most severe if a subject has multiple limitation events); and the 
proportion of subjects with any elevated brain natriuretic peptide (BNP) or troponins and 
elevation status.  


 
 
34 
 
8.3.5 
Clinical Laboratory Results 
Per protocol, samples for hematology, serum chemistry, and urinalysis will be collected at the 
following timepoints: Screening visit, day 1 of each cycle, EOT visit and at the 30-day post last 
dose visit. Samples for coagulation will be collected at the screening visit, and at day 1 of cycle 
1. All laboratory results will be converted into Système International (SI) units for analysis and 
graded using the laboratory reference ranges from individual laboratories and the criteria from 
NCI CTCAE (Common Terminology Criteria for Adverse Events, Version 5) by the Sponsor. If 
one or more normal ranges for a laboratory are missing, then a standard normal range from the 
Merck Manual will be used to perform toxicity grading.  
8.3.5.1 
Laboratory Results 
Listings of select laboratory results will be produced for all subjects by nominal visit and where 
appropriate, may include the change from baseline, laboratory toxicity grade, and reference 
range. Each abnormal value will be flagged to show whether it is a value below or above 
the reference range. Laboratory abnormalities will be summarized in a table using counts and 
percentages.  
8.3.5.2 
Laboratory Toxicities 
Laboratory toxicities by grade will be summarized using counts and percentages. For each 
graded laboratory test, only the worst (i.e., highest) toxicity grade will be counted for subjects 
with multiple toxicities within a time period (including scheduled and unscheduled assessments). 
For each graded laboratory test, shift tables will be produced to summarize the shift in toxicity 
grade from baseline to the worst treatment-emergent grade. In addition to summary tables, 
listings of laboratory test results may be provided for subjects with any Grade 3 or higher 
toxicities.  
 
Table 8: Toxicity Terms for Laboratory Parameters Graded for both High and Low values 
Analyte 
Term (high values) 
Term (low values)  
Calcium 
Calcium high 
Calcium low 
Blood glucose 
Blood glucose high 
Blood glucose low 
Potassium 
Potassium high 
Potassium low 
Sodium 
Sodium high 
Sodium low 
Hemoglobin 
Hemoglobin high 
Hemoglobin low 
Lymphocyte Count 
Lymphocyte count high 
Lymphocyte count low 


 
 
35 
 
Magnesium 
Magnesium high 
Magnesium low 
Phosphorous 
Phosphorous high 
Phosphorous low 
WBC 
White blood cell count high 
White blood cell low 
 
8.3.6 
Cardiac Function 
8.3.6.1 
Left Ventricular Ejection Fraction 
The following left ventricular ejection fraction (LVEF) endpoints will be summarized using 
counts and percentages. 
x LVEF result at baseline (<50%, ≥ 50%) 
x Minimum LVEF result post-baseline (<50%, ≥ 50%) 
x Minimum post-baseline LVEF result with a decrease of t10 percentage points or more 
from the baseline result 
x Post-baseline LVEF result that is < 50% with a decrease of t10% or more from the 
baseline result  
In addition, a shift table based on the <50% and ≥50% cut-offs will be used to summarize 
changes of the baseline LVEF values against the lowest treatment-emergent values. 
8.3.6.2 
ECG 
ECG interpretations (e.g., normal, or abnormal) will be summarized using counts and 
percentages. For abnormal ECG, the frequency of clinically significant findings will also be 
summarized using counts and percentages. The following QTcF interval endpoints will be 
summarized using counts and percentages:  
x QTcF interval increase from baseline (<30 milliseconds, 30–60 milliseconds, and >60 
milliseconds) during the treatment period. 
x QTcF interval prolongation <450 msec, 450-480 msec, >480 msec during the 
treatment period 
For both endpoints, the worst value for each subject during the treatment period (first dose date 
through the end of the safety reporting period, i.e. 30 days after the last dose of study treatment) 
will be summarized. 


 
 
36 
 
8.3.7 
Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be summarized 
using descriptive statistics (i.e., mean, median, standard deviation, and range). 
8.3.8 
ECOG Performance Status 
ECOG performance status over time will be listed by subject. The baseline status, best status 
post-baseline, worst status post-baseline, and status at end of treatment will be summarized using 
counts and percentages. 
8.3.9 
Post-Study Treatment Systemic Anti-Cancer Therapies 
Post-study treatment systemic anti-cancer therapies (i.e., subsequent treatment) will be coded 
using the World Health Organization Drug Dictionary (WHO-DD) summarized by preferred 
term using counts and percentages. Multiple occurrences of the same therapy within a subject 
will be summarized only once. 
8.4 
Quality of Life, Disease-Related Pain Analyses and Opioid Use 
Analysis of Quality-of-life endpoints will be based on the safety analysis set for cohort 1 and 
cohort 2 separately. 
 
 
 
  
 
 
   
 
 
 
 
 
 
  
 
 
 
  
 
CCI


 
 
37 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
CCI


 
 
38 
 
8.5 
Immunogenicity Analyses 
All immunogenicity analyses will be based on the immunogenicity analysis set described in 
Section 7.1. 
Subjects developing an anti-drug antibody response will be listed. Subjects ‘positive’ in Tier 1 
and Tier 2 will be listed along with their Tier 3 titers. If available, domain specificity data and 
anti-ZW25 neutralizing antibodies will be listed and summarized as well. 
The occurrence of anti-drug antibodies (ADAs) will be summarized using counts and 
percentages by nominal time point and by cohort. Titers for confirmed positive ADA will be 
summarized using descriptive statistics (e.g., n, geometric mean, geometric coefficient of 
variance).  When determining post-baseline incidence, patients are considered to be ADA 
positive if they are initially ADA negative at baseline and test positive for ADAs following study 
drug exposure (“treatment-induced ADA response”), or if they are ADA positive at baseline and 
the titer of one or more post-baseline samples is at least 4-fold greater than the titer of the 
baseline sample (“treatment-enhanced ADA response”).  Patients are considered to be ADA 
negative if they are ADA negative and all post-baseline samples are negative, or if they are ADA 
positive at baseline but do not have any post-baseline samples with a titer that is at least 4-fold 
greater than the titer of the baseline sample (“treatment unaffected”). Duration of antibody 
response is also monitored and identified as either “transient” (ADA positive result detected at 
only one post-baseline sampling timepoint [excluding last timepoint] or at 2 or more timepoints 
during treatment or safety follow-up where the first and last ADA positive samples are separated 
by a period of <16 weeks, irrespective of any negative samples in between) or “persistent” (ADA 
positive result detected at the last post-baseline sampling timepoint or at 2 or more timepoints 
during treatment or safety follow-up where the first and last ADA positive samples are separated 
by a period t16 weeks, irrespective of any negative samples in between). 
Additional analyses to evaluate the association between development of ADAs and 
efficacy/adverse events may also be performed based on treatment-emergent ADA results. 
8.6 
Pharmacokinetic Analyses 
All pharmacokinetic (PK) analyses will be performed on the Pharmacokinetics analysis set 
defined in Section 7.1. Pharmacokinetic sampling will be performed according to two different 
schedules. Table 9 presents the PK sampling timepoints for both extensive and sparse sampling.  
Table 9: PK Sampling time points for Zanidatamab  
Cycle number / Cycle length 
Day 
Time 
Point 
Time window 
Extensive 
Sparse 
1 / 28 days 
1 
Pre-dose 
 
X 
X 


 
 
39 
 
End of 
ZW25 
infusion 
+15 
min 
X 
X 
2 hours 
post-dose 
± 15 min 
X 
 
4 hours 
post-dose 
± 15 min 
X 
 
8 hours 
post-dose 
± 3 h 
X 
 
2 
24 hours 
post-dose 
±4 h 
X 
 
5 
96 hours 
post-dose 
±4 h 
X 
 
15 
Pre-dose 
– 4 h 
X 
X 
End of 
ZW25 
infusion 
+15 min 
X 
X 
Cycle 2 / 28 days 
1 and 
15 
Pre-dose 
– 4 h 
X 
X 
End of 
ZW25 
infusion 
+15 min 
X 
X 
Additional Even-Numbered 
Cycles a 
1 
Pre-dose 
– 4 h 
X 
X 
End of 
ZW25 
infusion 
+15 min 
X 
X 
EOT 
- 
- 
 
X b 
X b 
EOT = end of treatment; h = hour; min = minute; PK = pharmacokinetics; 
ZW25=Zanidatamab. 
Extensive sampling will be performed for the first 6 enrolled subjects only. 
a Day 1 of Cycles 4, 6, 8, 10, and 12. 
 
 
b Only required if subject has completed less than 6 months of treatment. 
 
Table 10: Steady-State Extensive Pharmacokinetic Sampling Schedule on Cycle 4 or any 
Subsequent Cycle 
Day 
Time Point 
Time window 
1 
Pre-dose 
 
End of zanidatamab infusion 
+15 min 
2 hours post-dose 
± 15 min 
4 hours post-dose 
± 30 min 
8 hours post-dose 
± 3 hours 
3 
48 hours post-dose 
± 1 days 
5 
96 hours post-dose 
± 1days 


 
 
40 
 
15 
336 hours post-dose 
± 3days 
Extensive sampling at steady state: Performed for the first 10 suitable subjects in China 
who reach Cycle 4 and the first 20 suitable subjects in the rest of world who reach 
Cycle 4 
8.6.1 
Serum Concentrations 
Peak and trough serum concentrations of zanidatamab will be summarized using descriptive 
statistics (e.g., n, mean, coefficient of variance) by nominal collection timepoint. Tabulations and 
graphs such as individual plots and mean plots may be presented. 
8.6.2 
Pharmacokinetic Parameters 
Serum concentrations of zanidatamab will be measured as a function of time post-dosing. 
For the extensive PK analysis set (dose 1 and steady-state), serum concentration-time data of 
each patient will be tabulated and graphically presented on linear and semilogarithmic scales. 
Pharmacokinetic parameters will be determined using standard noncompartmental method with 
actual collection time. 
For each subject, the parameters listed below will be reported when there is sufficient data 
available to support the accurate estimation of the parameter based on actual sample collection 
times. 
The following PK parameters will be derived for single (first) dose using extensive PK sampling 
data after dose 1: 
x 
AUClast  area under the serum concentration-time curve from zero to the last 
 
measurable concentration for dose 1 
x 
AUCtau,1 area under the serum concentration-time curve tau (the time from the start to     
the end of the dosing interval) for dose 1 
x 
AUCINF area under the serum concentration-time curve from zero to infinity for dose 1 
x 
Cmax,1  
maximum observed serum concentration for dose 1 
x 
Ctrough,1 
trough serum concentration for dose 1 
x 
t½  
terminal half-life for dose 1 
x 
CL 
serum clearance for dose 1 
x 
Vz 
volume of distribution in the terminal phase for dose 1 
The following PK parameters will be reported for extensive subjects with multiple dosing at 
steady-state using PK sampling data: 


 
 
41 
 
x 
AUCtau,ss  area under the serum concentration-time curve tau (the time from the start to 
the end of the dosing interval) at steady-state 
x 
Cmax,ss  
maximum observed serum concentration at steady-state 
x 
Ctrough.ss  trough serum concentration at steady-state 
x 
Cave,ss  
average concentration over the dosing interval, calculated as AUCtau/tau. 
Where tau is the dosing interval for Dose 1, at steady-state 
x 
t1/2,ss  
terminal half-life at steady-state 
x 
Vss  
volume of distribution at steady-state 
x 
Accumulation index for AUCtau and Cmax 
steady-state PK parameter value divided by 
the PK parameter value from dose 1 
x 
Peak-to-trough ratio: Cmax/Ctrough 
The following parameters will be derived and summarized for all subjects with either extensive 
or sparse sampling data: 
x RCtroughaccumulation index, calculated as Ctroughlast dose)/Ctroughfirst dose) 
x Ctrough,ss trough concentration at steady state 
PK parameters will be summarized using summary statistics (e.g., n, geometric mean, geometric 
coefficient of variance) by nominal timepoint. 
 
  
 
 
 
 
 
 
 
   
8.9 
Subgroup Analysis of Subjects Enrolled from China sites 
All the above analyses, including efficacy, PK, immunogenicity and safety will be conducted for 
subjects enrolled from China sites, unless otherwise specified. These analyses will be used for 
submission to the CDE. 
For efficacy analysis, there are 4 analysis sets that will be used for efficacy analysis for subjects 
enrolled from China sites. The primary efficacy analysis set includes subjects enrolled in Cohort 
CCI


 
 
42 
 
1 who received any amount of Zanidatamab. The other 3 efficacy analysis sets are supportive 
secondary analyses, with definition is provided in Table 11. A pooled analysis combining 
Cohorts 1 and 2 may be performed in addition, if a clinically meaningful treatment effect is 
observed for Cohort 2. 
For safety evaluation, subjects enrolled from China sites who received any amount of 
Zanidatamab will be used for safety analysis. 
In addition, trial conduct information will also be summarized for subjects enrolled from China 
sites. Trial conduct information includes screen failures and enrollment, subject disposition, 
protocol deviations, baseline demographic and disease history, prior systemic cancer therapy, 
radiotherapy and surgery, concomitant medications, and procedures. 
At the timing of analysis for the overall subject population, analyses for subjects enrolled from 
China sites will be performed concurrently with same cutoff date. The subgroup analysis of 
subjects enrolled from China sites may not be included in the clinical study report. 
Table 11: Analysis Sets for Efficacy Analysis for Subjects Enrolled from China sites 
Analysis Set  
Description  
Efficacy Analysis Set 
China Subgroup [E1] 
Includes subjects enrolled  from China sites who received any amount of 
zanidatamab.  
 Cohort 1: includes subjects enrolled in Cohort 1 from E1, this is the primary efficacy 
analysis set. 
Modified Efficacy 
Analysis Set China 
Subgroup [E2] 
Includes subjects enrolled from China sites who received any amount of zanidatamab 
and excludes intolerant subjects who are not adequately treated per NMPA CDE’s 
requirement.  
Cohort 1: includes subjects enrolled in Cohort 1 from E2, this is the secondary 
efficacy analysis set. 
Response Evaluable 
Analysis Set China 
Subgroup [RE1] 
Includes subjects enrolled from China sites who are response evaluable.  
 
A subject is considered response evaluable if they have measurable disease at 
baseline and at least 1 evaluable, post-baseline disease assessment (per RECIST 1.1) 
or discontinued study treatment due to death or unequivocal clinical progression and 
received any amount of zanidatamab. 
 
Cohort 1: includes subjects enrolled in Cohort 1 from RE1, this is the secondary 
efficacy analysis set. 
Modified Response 
Evaluable Analysis 
Set China Subgroup 
[RE2]  
Includes subjects enrolled from China sites who are response evaluable and excludes 
intolerant subjects who are not adequately treated per NMPA CDE’s requirement.  
 
 Cohort 1: includes subjects enrolled in Cohort 1 from RE2, this is the secondary 
efficacy analysis set.  
 
 
 


 
 
43 
 
9 
CHANGES IN THE PLANNED ANALYSIS 
The following changes and/or clarifications to the analysis described in the study protocol are 
described. 
 Change 
Reason for change 
Definition of treatment-emergent adverse 
event (TEAE). 
Protocol definition: “TEAEs are defined as 
events with an onset during or after receipt of 
the first dose of zanidatamab and up to and 
including 30 days after the last dose but prior 
to the start of a new anti-cancer therapy.” 
 
SAP definition: “TEAEs are defined as AEs 
with an onset during or after receipt of the 
first dose of zanidatamab and up to and 
including 30 days after the last dose.” 
The new definition in the SAP is more 
conservative than the definition in the study 
protocol. 
Table 4: Analysis Set 
Pharmacokinetics definition was modified to 
consider subjects who did not have a baseline 
sample 
Immunogenicity analysis set definition was 
added  
 
The new definition is more robust 
Section 8.6: Pharmacokinetics Analysis 
Definitions and analysis were added/clarified 
Added clarification 
Definition of PFS and DOR were updated to 
remove clinical progression as an event. 
To align with standard definition of PFS 
Definition of duration of response 
Clarified compared to protocol language that 
response (PR, CR) must be confirmed.  
Definition of disease control rate 
Clarified compared to protocol language that 
PR and CR must be confirmed. 
 


 
 
44 
 
 
 
10 REFERENCES 
1. Schwartz LH, Litière S, de Vries E, et al. RECIST 1.1-Update and clarification: From the 
RECIST committee. Eur J Cancer. 2016; 62:132–137. doi: 10.1016/j.ejca.2016.03.081 
2. Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 26: 404-413. 
3. Independent Review Charter. A Phase 2b, open-label, single-arm study of ZW25 
monotherapy in subjects with advanced or metastatic HER2-amplified biliary tract cancers. 
Version 1.0; Bioclinica: 03August2020. 
4. Brookmeyer, R. and Crowley, J. (1982) A confidence interval for the median survival time. 
Biometrics, 38, 29-41. doi:10.2307/2530286.  
5. Collett D (1994). Interval-censored survival data. Modelling survival data in medical 
research. Boca Raton, Fla., Chapman & Hall/CRC: 237-251. 
6. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026. 
7. Major Greenwood, Jr. (1926). The Natural Duration of Cancer. Reports of Public Health and 
Related Subjects, Vol. 33, HMSO, London. 
8. Guidance for Industry. Pharmacokinetics in Patients with Impaired Renal Function – Study 
Design, Data Analysis, and Impact on Dosing. September 2020, Clinical Pharmacology, 
Revision 2. 
9. Cockcroft, D.W. and M.H. Gault. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976. 16(1):31-41. 
10. Mohamed Elmeliegy et-al. Discordance Between Child-Pugh and National Cancer Institute 
Classifications for Hepatic Dysfunction: Implications on Dosing Recommendations for 
Oncology Compounds. The Journal of Clinical Pharmacology 2021, 61(1) 105–115 
11. Cleeland C.S. The Brief Pain Inventory, User Guide, 2009.