Clinical trial NCT04513665
Conditions: Endometrial Cancer Carcinosarcoma
Keywords: Endometrial Cancer Carcinosarcoma ZW25 20-162 Memorial Sloan Kettering Cancer Center
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2020-08-12; Completion date: 2024-03-08
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is being done to test the drug ZW25 and look at whether this drug is effective in women with HER2-overexpressed endometrial cancer or carcinosarcoma that has been treated in the past.

Detailed description:

Arms: arm 1: Participants will have recurrent endometrial carcinoma or carcinosarcoma with HER2 overexpression and 1-2 prior lines of chemotherapy. 16 participants will be accrued. If 2 or greater responses are seen, Stage 2 will accrue additional participants. arm 2: If 2 or greater responses are seen during Stage 1, Stage 2 will accrue an additional 9 participants. Participants will have recurrent endometrial carcinoma or carcinosarcoma with HER2 overexpression and 1-2 prior lines of chemotherapy.
Interventions: intervention 1: ZW25
Intervention descriptions: intervention 1: ZW25 at 20mg/kg intravenously (IV) every two weeks.

Protocol documents:
Prot_SAP_000.pdf: 
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IRB Number: 20-162 A(7) 
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Page 1 of 66 
 
 
MSK PROTOCOL COVER SHEET 
A Phase 2 Trial of ZW25 in HER2 Overexpressed Advanced Endometrial Cancers and 
Carcinosarcomas (ZW25-IST-2) 
 
Principal Investigator/Department: 
Vicky Makker, MD / Medicine 


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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................. 4 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................ 17 
4.1 
Design ......................................................................................................................... 17 
4.2 
Intervention ................................................................................................................. 18 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS ....... 19 
6.0 
CRITERIA FOR PARTICIPANT ELIGIBILITY .................................................................. 22 
6.1 
Participant Inclusion Criteria ........................................................................................ 22 
6.2 
Participant Exclusion Criteria ....................................................................................... 24 
7.0 
RECRUITMENT PLAN ................................................................................................... 27 
7.1 
Research Participant Registration ............................................................................... 28 
8.0 
INFORMED CONSENT PROCEDURES ......................................................................... 28 
9.0 
PRE-TREATMENT/INTERVENTION............................................................................... 29 
10.0 TREATMENT/INTERVENTION PLAN............................................................................. 30 
11.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................. 34 
12.0 CRITERIA FOR REMOVAL FROM STUDY .................................................................... 37 
13.0 
CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY .............. 37 
14.0 BIOSTATISTICS ............................................................................................................. 44 
15.0 TOXICITIES/RISKS/SIDE EFFECTS .............................................................................. 46 
15.1 Serious Adverse Event (SAE) Reporting ..................................................................... 52 
15.2. External SAE Reporting ................................................................................................ 53 
16.0 PROTECTION OF HUMAN PARTICIPANTS .................................................................. 54 
16.1 Privacy ........................................................................................................................ 55 
16.2 Data Management .......................................................................................................... 55 
16.3 Quality Assurance ....................................................................................................... 56 
16.4 Data and Safety Monitoring ......................................................................................... 56 
17.0 
REFERENCES ............................................................................................................... 57 
18.0 
APPENDICES ................................................................................................................ 64 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a Phase 2, open label study designed to evaluate the efficacy and safety of 
ZW25 in patients with advanced/recurrent HER2 overexpressed endometrial cancers 
and carcinosarcomas. Up to 25 patients will be enrolled on this study. 
The study will be conducted in two stages. Stage 1 will accrue 16 patients and if two or 
greater responses are seen, Stage 2 will accrue an additional 9 patients. In this study 
the recommended ZW25 dose will be 20mg/kg intravenously (IV) every two weeks. 
Treatment cycles will be 28 days. 
Patients will continue to receive study treatment until they present with progressive 
disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, 
develop unacceptable toxicity or withdraw consent, whichever comes first, or until the 
study is terminated. 
Tumor assessments, including radiological assessments by computerized tomography 
(CT) or magnetic resonance imaging (MRI) scans are performed at Screening and 
subsequently every eight weeks (from Cycle 1 Day 1) for the first 24 weeks and then 
every twelve weeks until PD, death or initiation of subsequent anti-cancer therapy, 
whichever occurs first. All patients who discontinue study treatment for any reason are 
followed every 3 months until death, lost to follow up, or withdrawal of consent, for 
survival follow up for up to 2 years. 
 


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Abbreviations – IV: intravenous, ORR: Overall response rate, PFS: Progression-free 
survival, OS: Overall survival, CBR: Clinical benefit rate, DOR: Duration of response 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objective: 
 
To determine Overall Response Rate [ORR = Complete Response (CR) + Partial 
Response (PR)] by RECIST v 1.1 ≤ 24 weeks from the start of treatment 
Secondary Objectives: 
 
To determine Progression Free Survival (PFS) rate at 24 weeks 
 
To determine Clinical Benefit Rate (CBR) by 24 weeks 
 
To determine PFS and Overall Survival (OS) 
 
To determine Duration of Response (DOR) 
 
To determine the rate of Serious Adverse Events (SAE) of ZW25 by Common 
Terminology Criteria for Adverse Events version 5 (CTCAE v 5.0) 
Exploratory Objectives: 
1. Anti-drug antibodies (ADA) will be assessed at baseline (baseline ADA can be collected 
on C1D1 pre dose) and pre-dose at Cycles 2, 4, 6, 8, 12, 18, 24 Day 1. The 
immunogenicity testing will be performed using validated assays 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 further titrated to 
determine the titer of ADA. 
2. To explore the molecular associations between the HER2 biomarkers: gene 
amplification (by Next Generation Sequencing [NGS] and in situ Hybridization [ISH]), 
protein overexpression by immunohistochemistry (IHC) and mutational status and/or 
copy # variations of relevant cancer-related genes using MSK-IMPACT platform in all 
patients with new research biopsies collected under this protocol, and to determine 
mechanisms of underlying response and resistance. Mandatory pre-treatment and post- 
treatment (collected upon progression of disease) tumor biopsies will be obtained on all 
patients for this purpose. Tissue testing will be performed in the Center for Molecular 
Oncology. 
3. To examine ORR in each cohort by different types of molecular alterations, HER2 
amplification (by NGS and ISH separately), mutation and HER2 overexpression, and 
assess genomic changes with response for potential predictive signatures. 
4. To evaluate the predictive value of changes in circulating tumor DNA variant allele 
frequency during treatment for response to ZW25. 


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3.0 
BACKGROUND AND RATIONALE 
HER2 DEPENDENCY 
HER2 is a member of the 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 (1). HER2 is unique among HER family members in that it has no known 
ligand, and maintains a dimerization-ready conformation. HER2 is the preferred 
dimerization partner for other HER family members. HER2-containing heterodimers, 
particularly HER2/HER3, deliver the most potent growth signals (2). 
The HER2 gene, which encodes a member of the erbB family of receptor tyrosine 
kinase, has been described as a key oncogenic driver in numerous malignancies. HER2 
amplification is an oncogenic driver event which is found in approximately 20% of breast 
cancers and the successful application of HER2 targeted therapy in phase 3 randomized 
controlled trials has revolutionized the care and altered prognosis of these patients (5, 
25, 27, 35, 36). Additionally, approximately 15-20% of gastroesophageal cancers are 
HER2 amplified and the addition of trastuzumab to chemotherapy in these patients was 
shown to improve overall survival (6). Databases from The Cancer Genome Atlas 
(TCGA), our institution and others have demonstrated HER2 amplifications in a variety 
of solid tumor cancers, including lung, bladder, endometrial and other cancers (Figure 1) 
(7-13 , 37, 38). HER2 amplification occurs in 2-10% of lung cancers, 6% of bladder 
cancers, 5-12% of endometrial cancers and 2-5% of ovarian and colorectal cancers (7- 
15). High level HER2 protein overexpression by immunohistochemistry (IHC 3+) is a 
validated surrogate marker for gene amplification (4-6). HER2 amplification or HER2 
overexpression in lung, bladder and endometrial cancers is associated with poor 
prognosis and these patients are in need of more effective systemic therapy (15-18). 
Furthermore, HER2 mutations including insertions/deletions and point mutations in the 
kinase and extracellular domains occur in 2-3% of lung cancers and have been identified 
as oncogenic drivers (7, 8, 19, 20). Preclinical models have shown the inhibitory effects 
of single agent trastuzumab on HER2 mutant lung cancer cell lines (21, 22) and clinical 
series of patients with HER2 mutant lung cancer have reported high response rates from 
trastuzumab based therapy (23, 24). 
HER2 mutations also occur in approximately 6% of bladder cancer and 2-5% of 
endometrial, ovarian, breast, gastric and colorectal cancers (7, 8, 9, 10, 12, 14, 19, 39- 
41). The discovery of HER2 mutations in many solid tumors has led to speculations of 
their association with HER2 amplification and their clinical significance as an oncogenic 
driver and independent therapeutic target (7-11, 12, 14, 19-22, 39, 41). Preclinical 
studies have demonstrated activity of neratinib, afatinib, dacomitinib and trastuzumab in 
HER2 mutant lung and breast cancer cell lines (21, 22, 42-45). This has led to several 
phase 2 clinical trials in HER2 mutant lung and breast cancers and the off label use of 


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HER2 targeted therapies in these patients (23, 24). Despite the availability of a variety of 
HER2 targeted therapies, the molecular relations between HER2 amplification and 
mutation, and their true clinical implications remain unknown. This presents an urgent 
need for translational and clinical research in HER2 biomarkers and HER2 dependent 
cancers. 
 
 
Figure 1: 
 
HER2 in Endometrial Carcinomas and Carcinosarcomas 
 
Endometrial cancer (EC) is the most common gynecologic malignancy in the United 
States. The incidence of endometrial cancer in the United States has been estimated to 
be 63,230, with approximately 11,350 endometrial cancer related deaths in 2018 (46). 
ECs are typically defined as Type I and Type II cancers. Type I endometrial cancer 
accounts for 80% of the cases. This more indolent type is associated with endometrioid 
histology, retention of hormone receptor status, and younger age of onset (47). Type II 
tumors are associated with serous, clear cell or grade 3 endometrioid histology, loss of 
hormone receptor status, black race, and presentation at a later stage. Type II 
endometrial cancers portend typically poorer prognosis due to their aggressive biology 
and presentation at an advanced stage (48, 49). Uterine serous carcinoma (USC) 
accounts for 3-10% of all endometrial cancers; however, it is responsible for 39% of the 
endometrial cancer-related mortality (50). Uterine carcinosarcomas (UCS) account for 


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less than 5% of all uterine malignancies and are high grade endometrial carcinomas 
whose molecular phenotype overlaps with uterine serous carcinomas. (51) UCS 
accounts for 15% of all deaths caused by uterine corpus malignancy (52). 
 
The mainstay of conventional therapy for USC and UCS is a combination of 
comprehensive surgical staging, including peritoneal washings, total hysterectomy, 
bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, 
omentectomy, and peritoneal biopsies followed by adjuvant therapy. Both USC and UCS 
carries a high rate of recurrence of extra-pelvic metastases, even in early-stage disease 
(48). Thus, adjuvant therapy is routinely administered in both early and advanced USC 
and UCS in the form of either chemotherapy, radiotherapy, or both (52-54); however, the 
optimal regimen has yet to be determined in the prospective setting. 
 
Current management of advanced stage endometrial cancer is comprised of platinum 
and taxane-based chemotherapy. 
 
Based on GOG- 209, a randomized phase III trial designed to compare carboplatin and 
paclitaxel (CT) to the triplet doxorubicin, cisplatin and paclitaxel (TAP) regimen, CT was 
not inferior to TAP in terms of PFS (4 months in both arms) and OS (32 vs 38 months, 
respectively; HR 1.01).(74) The toxicity profile for CT was significantly more favorable, 
and this regimen serves as the acceptable backbone for future chemotherapy trials in 
advanced chemotherapy-naïve endometrial carcinomas. This regimen is now the gold 
standard front-line chemotherapy regimen in advanced endometrial carcinomas. 
Following front-line CT chemotherapy, only megestrol acetate for the palliative treatment 
of advanced (and primarily low grade endometrioid endometrial carcinomas) and 
pembrolizumab for MSI-H/dMMR recurrent (Based on Phase Ib trial KEYNOTE- 
028/016/158 evaluating response rates in patients with MSI-H or MMR-d solid tumors 
where an objective response rate of 46% was seen in the endometrial cancer cohort 
(76)) endometrial cancers are approved therapies for endometrial carcinomas. However, 
for serous and serous-like endometrial carcinomas which are known to be MSS and also 
unresponsive to hormonal therapy, options are quite limited, and novel therapies are 
needed. 
Critical to moving treatment forward for women with advanced uterine serous 
carcinomas and uterine carcinosarcomas is the identification of actionable opportunities. 
HER2 over expression is one such target in these highly malignant endometrial cancer 
subtypes, and this background serves as a basis for this current trial. 
 
ECs harbor specific molecular alterations which make this disease site an attractive 
ground for targeted therapies (55). Most investigators agree that low-grade (i.e., TCGA 
copy number low-tumors) and high-grade endometrial cancers (i.e., TCGA copy number 
high-tumors) are two distinct entities, with significantly different drivers of neoplasia. 
Along these lines, Type I cancers often have molecular alterations of phosphatase and 
tensin homolog tumor suppressor (PTEN) (30-80%), beta-catenin (20-50%), and Ras 
(25%) (56, 57). Oncogenic alterations in the phosphatidylinositol-3-kinase (PI3K) 


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pathway appear to affect both Type I and Type II cancers (56). PI3K pathway alterations 
are not only mutual for both types, but are also one of the most frequently detected 
mutations (30-50%) in endometrial cancers, strongly suggesting that targeted therapies 
altering this crucial pathway might have significant therapeutic implications (58). Type II 
cancers, on the other hand, most commonly demonstrate mutations in the TP53 gene 
(up to 90%) (57). Recent comprehensive whole-exome sequencing studies carried out 
by TCGA and by our group have reported HER2/PI3K pathway as one of the most 
altered pathways in USC with HER2/neu gene amplification identified in 27% and 44% of 
USC and in 11% of UCS (51) , respectively, supporting HER2 as an attractive pathway 
for novel targeted therapies (55). Importantly, Buza et al. (59) evaluated HER2 
overexpression in 108 cases of USC prospectively tested at Yale University by 
immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) assays. This 
study revealed that over half (i.e., 53%) of the HER2 overexpressing tumors (i.e., overall 
35% showed HER2 overexpression at 3+ level by IHC and/or gene amplification) had 
significant heterogeneity of protein expression by IHC. Furthermore, in contrast to breast 
carcinomas, USC showed a lateral or basolateral (’U-shaped’) cellular distribution 
pattern previously observed in gastric/gastroesophageal junction carcinomas. 
 
HER2 as an Oncogenic Target for Advanced/Recurrent USC and UCS Patients 
 
When HER2 is activated by dimerizing with either HER1 (heterodimer), HER2 
(homodimer), HER3 (heterodimer), or HER4 (heterodimer), a cascade of responses are 
set into motion within the cell through the EGF-tyrosine kinase, PI3K/Akt, and 
Ras/Raf/MAPK pathways (60). These intracellular pathways act to alter angiogenesis, 
cell proliferation, and metastasis (61). Overexpression and amplification of the HER2 
protein and HER2/neu, respectively, play a major role in carcinogenesis, treatment, and 
outcomes in USC, making HER2 an excellent target for precision medicine (62). 
Accordingly, precision medicine was recently employed in a randomized phase II trial 
where a HER2-targeting antibody (trastuzumab) was added to standard chemotherapy 
in the treatment of 61 USC patients with stage III-IV or recurrent disease overexpressing 
HER2/neu. Trastuzumab combined with carboplatin and paclitaxel chemotherapy 
demonstrated a significant improvement in progression-free survival in both advanced 
and recurrent USC patients while toxicity was not different between treatment arms (54). 
This practice-changing randomized study represents the first prospective trial in 
endometrial cancer targeting USC exclusively and the largest randomized trial report to 
date to describe the activity of trastuzumab in HER2-overexpressing USC (54). 
 
Mechanism of Resistance to HER2-targeted Therapy Active in USC 
 
Despite promising preclinical and clinical results with HER2-targeted therapy in USC, 
similarly to breast cancer patients treated with trastuzumab, acquired resistance may 
ultimately develop (54, 63). Primary or secondary resistance to single-agent trastuzumab 
has been reported in up to 70% of HER2-overexpressing breast cancer patients treated 
with trastuzumab (64) and several mechanisms of resistance have been described in 
both breast cancer and USC patients. The main mechanisms of resistance currently 
identified in USC are: 1) overgrowth of HER2/neu negative cells (i.e., 0-1+ positive by 


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IHC) under trastuzumab selective pressure in HER2/neu heterogeneous tumors, 2) 
HER2/neu extracellular domain shedding or alterations in antibody binding site, 3) 
activation of downstream growth and survival pathways, and 4) overexpression of 
alternative HER ligands or receptors (65). 
 
Strategies to Overcome Resistance 
 
As discussed above, heterogeneity in HER2/neu expression in USC patients may 
represent a major mechanism of primary resistance to trastuzumab. Consistent with this 
view, single-agent trastuzumab treatment in HER2/neu-overexpressing endometrial 
cancer patients with recurrent disease was unable to induce any clinical response in 
patients (68). In contrast, highly encouraging results have recently been reported in 
advanced/recurrent USC patients treated with a combination of trastuzumab and 
carboplatin/paclitaxel chemotherapy. These data suggest for the first time that the 
combination of cytotoxic chemotherapy with a highly targeted agent (i.e., trastuzumab) 
may have strong synergistic activity in USC patients overexpressing HER2/neu 
regardless of the high heterogeneity in HER2 expression commonly detected in these 
rare but highly aggressive tumors (54). Another strategy we can envision to efficiently 
overcome the obstacle of HER2/neu heterogeneity in USC patients is represented by the 
use of novel HER2/neu-targeted ADC compounds and agents that target multiple HER2 
epitopes. These strategies may potentially overcome the obstacle of high heterogeneity 
in HER2/neu expression and limit the development/selection of HER2/neu negative 
clones during trastuzumab-based treatments. 
 
ZW25 
 
ZW25 is a novel, humanized bispecific antibody directed against 2 distinct HER2 
epitopes, extracellular domain 4 and 2 of the HER2 receptor (ECD4 and ECD2), the 
epitopes bound by trastuzumab and pertuzumab, respectively (Figure 2). Simultaneous 
binding of these two non-overlapping epitopes (known as biparatopic binding) results in 
dual HER2 signal blockade, including growth-factor mediated signaling, increased 
binding and removal of HER2 protein from the cell surface relative to trastuzumab, and 
potent immune effector function. ZW25 therefore has the potential to have greater 
activity than either trastuzumab or pertuzumab in HER2-expressing tumors. 


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IRB Number: 20-162 A(7) 
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Figure 2: 
ZW25 Structure 
 
 
 
Fab = fragment antigen-binding arm of antibody; 
Fc = fragment crystallizable; 
IgG1 = immunoglobulin G antibody isotype 1; 
scFv = single-chain variable fragment. 
 
Table 1. 
Chemical Name and Other Names 
 
Chemical Abstract Service (CAS) Number 
2169946-15-8 
Chemical Name(s) 
ZW25 
Company or Laboratory Code 
v10000 (variant designation at Zymeworks 
Inc.) 
Generic Name 
NA 
INN Name 
NA 
USAN Name 
NA 
INN = International Nonproprietary Name; NA = not applicable; USAN = United States Adopted Name 
 
Rationale for Studying ZW25 in Endometrial Cancers 
Despite the gains obtained with current HER2-directed therapy, medical need remains 
for patients with all HER2-expressing cancers, particularly with recurrent or metastatic 
disease that has progressed after standard of care therapy. This includes HER2 
overexpressing epithelial uterine malignancies. 
HER2-targeted therapies have not been approved for indications other than breast or 
gastric cancers. Several studies have evaluated HER2-targeted therapies, including 
trastuzumab or pertuzumab in some of these indications. Many of these studies did not 
specifically select for patients with HER2 IHC 3+ expression or gene amplification and 


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have not demonstrated clinical benefit (69, 70; 71, 72,). Challenges to the success of 
HER2-targeted therapy in non-breast/non-gastric indications include small numbers of 
patients, criteria for patient selection, increased heterogeneity of HER2 expression 
compared with breast cancer, and differences in tumor biology, including the relative 
importance of HER2-mediated signaling in maintaining tumor growth. Notably, in studies 
with stringent patient selection and dual HER2-targeting, encouraging results have been 
seen (73). Developing a single multifunctional antibody that has improved capacity and 
efficiency for binding HER2 compared with available HER2 inhibitors, and that can 
activate ADCC, block ligand induced heterodimerization of HER2 with other EGFR/ErbB 
receptors, and down-regulate HER2 may be the key to creating effective HER2-targeted 
therapies for HER2-expressing tumors. 
Trastuzumab combined with chemotherapy is superior to trastuzumab monotherapy and 
is well tolerated in the treatment of patients with HER2 overexpressing advanced breast 
cancer (HERCEPTIN®). Similarly, ZW25 may offer better efficacy in combination with 
other anti-cancer drugs with a favorable safety profile. In preclinical studies, ZW25 was 
demonstrated to have additive to synergistic anti-tumor activity with a number of different 
chemotherapeutic agents, including platinum agents, taxanes, receptor tyrosine kinase 
inhibitors, and DNA synthesis inhibitors in various HER2-expressing tumor cells. In 
patient-derived and tumor cell line-derived tumor xenograft models, ZW25 demonstrated 
promising anti-tumor activity that was superior to that observed with trastuzumab in a 
wide variety of HER2-expressing tumors, including those with low levels of HER2 
expression such as in a model of breast or NSCLC cancer. In a GLP repeat-dose 
toxicology study, ZW25 was well tolerated and no adverse effects were observed at 
doses up through 150 mg/kg administered as weekly IV infusions for up through 13 
weeks. Based on these findings, ZW25 is being evaluated in a first-in-human clinical 
study in patients with locally advanced (unresectable) and/or metastatic 
HER2-expressing cancers. Additionally, ZW25 is being explored in combination with 
standard first-line chemotherapy agents in HER2-expressing gastroesophageal 
adenocarcinoma (GEA). 
Pharmacology studies demonstrated that ZW25 binds HER2 with subnanomolar affinity, 
induces enhanced tumor cell binding, and blocks growth factor induced tumor growth 
(likely blocking HER2 heterodimerization with other epidermal growth factor receptor 
(EGFR)/ErbB family members). ZW25-induced cross-linking of HER2 also results in 
HER2 clustering and likely enhanced receptor internalization and down-regulation, as 
well as antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro studies 
demonstrate that ZW25 is synergistic and/or additive with chemotherapeutic agents in 
inhibiting the growth of human cancer cell lines that express high to low levels of HER2. 
In vivo studies demonstrated anti-tumor activity and/or improved host survival against 
xenografts of human breast, head and neck squamous cell (HNSCC), non-small cell 


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lung (NSCLC), pancreatic, gastric, and ovarian cancers in nude mice. Further, ZW25 
was efficacious in combination with chemotherapeutics in NSCLC, HNSCC and 
pancreatic cancer xenograft models in nude mice. 
Based on the results from the toxicology studies, the nonclinical safety assessment 
program supported evaluation of ZW25 as an IV infusion in the clinic. Therefore, a first- 
in-human clinical study was initiated. This ongoing study of ZW25 (ZWI-ZW25-101) is a 
3-part Phase 1 study, to evaluate the safety, tolerability, PK, immunogenicity, and 
preliminary anti-tumor activity of ZW25 as a single agent and in combination with 
selected chemotherapy agents in patients with locally advanced (unresectable) and/or 
metastatic HER2-expressing tumors. 
Additionally, a Phase 2, open-label, first-line study (ZWI-ZW25-201) has been initiated to 
investigate the safety, tolerability, and anti-tumor activity of ZW25 plus physician’s 
choice of combination chemotherapy in patients with unresectable, locally advanced, 
recurrent or metastatic HER2-expressing GEA. Physician’s choice of combination 
chemotherapy includes 3 globally-recognized, multi-agent, first-line treatment regimens: 
1) XP, which consists of capecitabine plus cisplatin; 2) 5-FU and leucovorin (FP), which 
consists of fluorouracil (5-FU) and leucovorin (folinic acid) plus cisplatin; or 3) 
mFOLFOX6, which consists of 5-FU and leucovorin plus oxaliplatin. 
Pharmacology36 
ZW25 has low nanomolar affinity to recombinant HER2 that was comparable to the 
binding affinities of trastuzumab and pertuzumab for HER2. It has low nanomolar binding 
affinity to cultured human cancer cells that express high to low levels of HER2. ZW25 
was shown to bind HER2 in a trans-configuration, resulting in clustering of HER2 
molecules and likely the enhanced internalization of HER2 observed compared with 
trastuzumab. In vitro studies demonstrated that ZW25 caused significant inhibition of the 
growth of human cancer cell lines that express high to low levels of HER2, inhibition of 
growth factor-mediated tumor cell proliferation, and synergy and additivity with 
chemotherapeutic agents in inhibiting the growth of human cancer cell lines that express 
high to low levels of HER2. ZW25 was shown to have affinity to Fcγ receptors equivalent 
to or greater than wild-type IgG1 and could induce ADCC activity at nanomolar 
concentrations against cancer cells that express high to low levels of HER2. In vivo 
studies demonstrated anti-tumor activity and/or improved host survival against 
xenografts of human breast, HNSCC, NSCLC, pancreatic, gastric, and ovarian cancers 
in nude mice. Further, ZW25 was efficacious in combination with chemotherapeutics in 
NSCLC, HNSCC, and pancreatic xenograft models in nude mice. 


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Results of in vitro and in vivo nonclinical pharmacodynamic studies as briefly detailed 
below support the investigational use of ZW25 alone or in combination with 
chemotherapy. 
Pharmacology studies are further detailed in the ZW25 Investigator’s Brochure. 
Nonclinical studies 
Pharmacology studies demonstrated that ZW25 binds HER2 with subnanomolar affinity, 
induced enhanced tumor cell binding, and blocks growth factor induced tumor growth 
(likely blocking HER2 heterodimerization with other EGFR/ErbB family members). 
ZW25-induced cross-linking of HER2 also resulted in HER2 clustering and likely 
enhanced receptor internalization and down-regulation, as well as ADCC. In vitro studies 
demonstrated that ZW25 caused significant inhibition of the growth of human cancer cell 
lines that express high to low levels of HER2, inhibition of growth factor-mediated tumor 
cell proliferation, and synergy and/or additivity with chemotherapeutic agents in inhibiting 
the growth of human cancer cell lines that express high to low levels of HER2. ZW25 
was shown to have affinity to Fcγ receptors equivalent to or greater than wild-type IgG1 
and could induce ADCC activity at nanomolar potency against cancer cells that express 
high to low levels of HER2. In vivo studies demonstrated anti-tumor activity and/or 
improved host survival against xenografts of human breast, HNSCC, pancreatic, gastric, 
and ovarian cancers in nude mice. 
The nonclinical testing strategy for ZW25 followed the ICH S9 guidance on nonclinical 
testing for anti-cancer pharmaceuticals and the ICH S6(R1)1 guidance for 
biotechnology-derived pharmaceuticals. 
Safety pharmacology, including an assessment of its effect on cardiovascular and 
respiratory function was conducted following dosing as part of the GLP toxicology study, 
as outlined in ICH S9. ZW25 showed no effect on safety pharmacology parameters. In 
addition, in vitro studies demonstrated that ZW25 had a similar effect as trastuzumab on 
human cardiomyocyte viability. 
Toxicology 
ZW25 has been evaluated in a comprehensive toxicology program (non-GLP and GLP 
studies). The toxicology program was carried out in cynomolgus macaque monkeys, as 
it was demonstrated that ZW25 bound both human and monkey HER2 with similar 
subnanomolar affinity, but did not bind to rodent HER2. Results of these studies 
supported the first-in-human (FIH) trial exploring the safety and tolerability of ZW25 
Toxicology studies are further detailed in the ZW25 Investigator’s Brochure. 


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3.6 Clinical Studies of ZW25 
The first-in-human clinical study was initiated on September 2016. This ongoing study of 
ZW25 (ZWI-ZW25-101) is a 3-part Phase I study, to evaluate the safety, tolerability, PK, 
immunogenicity, and preliminary anti-tumor activity of ZW25 as a single agent and in 
combination with selected chemotherapy agents in patients with locally advanced 
(unresectable) and/or metastatic HER-2 expressing tumors. 
Part 1 of the ZWI-ZW25-101 study is using a standard 3+3 dose-escalation design to 
determine the maximum-tolerated dose (MTD), optimal biological dose (OBD), or 
recommended dose(s) (RDs) of ZW25 monotherapy administered weekly (QW), once 
every 2 weeks (Q2W), and/or once every 3 weeks (Q3W) in patients with any HER2- 
expressing cancer that has progressed after receipt of all therapies known to confer 
clinical benefit. Part 2 of the study is characterizing the safety, tolerability, and 
preliminary anti-tumor activity of ZW25 monotherapy administered at the Part 1 MTD, 
OBD, or RD in patients with selected HER2-expressing locally advanced (unresectable) 
and/or metastatic cancers in up to 5 disease specific expansion cohorts, including 
HER2-high breast cancer (immunohistochemistry (IHC) 3+, or IHC 2+/ fluorescent 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 cancers. The recommended single-agent dose for further study was 
identified in Part 1 of the study as 20 mg/kg Q2W. Part 3 of the study is evaluating the 
safety, tolerability and preliminary anti-tumor activity of ZW25 administered in 
combination with selected chemotherapy agents, including paclitaxel, capecitabine and 
vinorelbine, in patients with HER2-expressing breast and GEA. 
As of 31 October 2018, a total of 67 patients have been enrolled and treated in Parts 1 
and 2 of the study (5 mg/kg QW, n=3; 10 mg/kg QW, n=13; 15 mg/kg QW, n=7; and 20 
mg/kg Q2W, n=44). Across all dose levels, the median age is 59 years (range, 2779). 
More patients are female (74.6%) than male (25.4%), the majority are white (76.1%), 
and the majority have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 1 (73.1%). There are no notable differences in demographics or baseline 
characteristics between dose levels. Most patients have a disease diagnosis of breast 
cancer (n=39, 58.2%). Additionally, 9 patients (13.4%) have gastric cancer, 4 each 
(6.0%) have esophageal or colorectal cancer, and 2 (3.0%) have gall bladder cancer. 
Other disease diagnoses in 1 patient each include adenocarcinoma of the sigmoid colon, 
cholangiocarcinoma, undifferentiated adnexal carcinoma of the skin, and bladder, 
cervical, endometrium, fallopian tube, parotid, and rectum cancers. Overall, nearly all the 
patients have disease with HER2-high expression (IHC 3+ or IHC 2+/FISH+) by local or 
central review (85.1%). Disease characteristics are generally similar between dose 
levels. Most patients have received prior HER2-targeted therapies, with 59 (88.1%) 
receiving trastuzumab (HERCEPTIN®), 36 (53.7%) receiving pertuzumab (PERJETA®), 
39 (58.2%) receiving ado-trastuzumab emantasine (KADCYLA®), 18 (26.9%) receiving 
lapatinib (TYKERB®), and 1 (1.5%) receiving neratinib (NERLYNX®). 


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Approximately one-third of the response-evaluable patients treated with single-agent 
ZW25 in Parts 1 and 2 of the study have achieved an objective response (n=15/48 
[31.3%]; all partial responses [PRs]) and approximately two-thirds of patients have 
experienced disease control (n=32/48 [66.7%]; 15 PRs and 17 stable disease). 
Regardless of dose level of ZW25, 17 patients (60.7%) with breast cancer have 
experienced disease control, including 8 with a PR and 9 with stable disease. Six 
patients (66.7%) with GEA have experienced disease control, 4 with PR and 2 with SD. 
Nine additional patients (81.8%) with other cancers also have experienced disease 
control, including 2 PRs and 3 SDs in colorectal cancer (CRC), 2 PRs in gall bladder 
cancer, 1 PR in cholangiocarcinoma, and 1 SD each in fallopian tube cancer, 
endometrium cancer, and parotid cancer. 
The updated data from this study was presented at ESMO 2019, where safety and 
preliminary anti-tumor activity data on 43 patients was presented (D-Y. Oh et al, ESMO 
2019 Annals of Oncology, Volume 30, Issue Supplement_9). In this study a total of 43 
patients were treated, including 17 patients with gastroesophageal adenocarcinoma, 6 
with biliary cancers, 10 with colorectal cancer, and 10 other cancers, including 3 
endometrial cancers. Fifty-nine percent of patients had prior HER2 therapy to include 
trastuzumab (59%), pertuzumab (10%), TDM-1 (7%), lapatinib (3%) and Neratinib (1%). 
The median number of prior therapies was 3 (range 1-6) for all patients. The most 
common treatment-related adverse events (all Grade 1 or 2) were diarrhea (49%) and 
infusion related reaction (34%). The objective response rate (all partial response (PR)) 
for response evaluable patients was 41% (14/34), and 38% of patients experienced 
stable disease (SD). The majority of patients (74%; 25/34) experienced a decrease in 
the sum of diameters for their target lesions. Compared to FISH, the positive predictive 
value of HER2 amplification in pre-dose C1D1 ctDNA was 90% (95% CI 79-96%), 
negative predictive value 45% (25-67%), and diagnostic accuracy 79% (63-90%). 
 
ZW25 Adverse Events 
In Parts 1 and 2 of the study, adverse events (AEs) occurring in 15% of patients treated 
with single-agent ZW25 across all dose levels include diarrhea (49.3%), infusion-related 
reaction (40.3%), fatigue (34.3%), nausea (23.9%), decreased appetite (17.9%), and 
headache (16.4%). Diarrhea (44.8%) and infusion-related reactions (40.3%) are the 
most common AEs considered to be related to ZW25 treatment. Other treatment-related 
AEs occurring in 15% of patients include fatigue (17.9%) and nausea (16.4%). Overall, 
most AEs have been Grade 1 or 2 (>90%). Grade 3 AEs occurring in more than 2 
patients include diarrhea, fatigue, and pleural effusion (n=3 each, 4.5% each); 2 of the 3 
patients with Grade 3 diarrhea and the 3 patients with Grade 3 fatigue had events that 
were considered to be related to ZW25. No treatment-related Grade 4 or 5 AEs, no 
dose-limiting toxicities (DLTs), and no treatment-related serious adverse events (SAEs) 
have occurred on study. Additionally, no treatment-related cardiac events have occurred 
thus far on study. Four patients have experienced cardiac events, including bradycardia, 
tachycardia, sinus tachycardia, and pericardial effusion, all considered unrelated to 
ZW25 and Grade 1 in severity. The Grade 1 event of worsening pericardial effusion 
occurred during screening (i.e., before taking any study drug) and was deemed serious 


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(required hospitalization) and related to pre-existing condition, but subsequently resolved 
after ECHO guided pericardiocentesis. An SAE of Grade 3 troponin I increased (of 
unclear etiology but most likely disease progression) was reported in a 36-year-old male 
patient with metastatic esophageal cancer after the patient discontinued treatment with 
ZW25. Troponin testing was performed as part of evaluation for inclusion in a different 
clinical study. The patient was observed in the ER and was asymptomatic. The event 
was considered recovered with sequelae the same day after serial troponin tests 
eventually plateaued and the patient was sent home. A stress test on the following day 
noted normal left ventricular ejection fraction and mild myocardial ischemia with no 
myocardial injury and no elevation in troponin I. 
Preliminary analysis of ADA present in the serum of patients in the dose-escalation 
phase showed that 9 of 13 patients had pre-existing ADA at baseline, and 2 patients had 
evidence of ADA by the second dose. Thereafter, no patients had evidence of ADA 
beyond the second dose of ZW25. One patient death occurred within the 30-day safety 
reporting period; however, the death was due to disease progression. Nine other 
patients have died on study, 8 due to disease progression and 1 due to an unrelated 
event reported as sudden death. 
In Parts 1 and 2 of the study, 83.6% of patients have experienced a treatment related 
TEAE. Similar to TEAEs overall, the most common treatment-related TEAEs include 
diarrhea (44.8%), infusion-related reaction (40.3%), fatigue (17.9%), and nausea 
(16.4%). 
In Parts 1 and 2 of the study, a total of 25 patients had 33 Grade 3 or higher TEAEs. 
Events occurring in 2 or more patients treated with ZW25 monotherapy across all dose 
levels include diarrhea, fatigue, and pleural effusion in 3 patients each (4.5% each), and 
anemia, decreased appetite, headache, malignant pleural effusion, pneumonia, and 
small intestinal obstruction in 2 patients each (3.0% each). 
Nearly all events were considered to be unrelated to study drug (94.0%). Four patients 
had events that were considered by the investigator to be related to treatment with 
ZW25, including fatigue (n=3/67, 4.5%), diarrhea (n=2/67, 3.0%), arthralgia, and 
hypophosphatemia (n=1/67, 1.5% each). Additionally, all events were Grade 3 in 
severity with the exception of an unrelated Grade 4 SAE of lung infection and an 
unrelated Grade 5 SAE of sudden death. 
As of the data cut-off date, in Parts 1 and 2 of the ongoing ZWI-ZW25-101 study, 
10 patients have died, 9 due to disease progression and 1 due to sudden death 
considered unrelated to ZW25. 
Efficacy analyses are ongoing for study ZWI-ZW25-101. Efficacy assessments are 
based on investigator assessment of response per response evaluation criteria in solid 
tumors (RECIST) v1.1. Overall, approximately one-third of the patients on ZW25 
monotherapy in Parts 1 and 2 of the study achieved an objective response (n=15/48, 
31.3%; all PRs) and approximately two-thirds of patients experienced disease control 
(n=32/48, 66.7%; 15 PRs and 17 stable disease). 


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For Parts 1 and 2 of the study regardless of dose level of ZW25, 17 patients (60.7%) 
with breast cancer experienced disease control, including 8 with a PR and 9 with SD. Six 
patients (66.7%) with GEA experienced disease control, 4 with PR and 2 with SD. Nine 
additional patients (81.8%) with other cancers also experienced disease control, 
including 2 PRs and 3 SDs in colorectal cancer (CRC), 2 PRs in gall bladder cancer, 1 
PR in cholangiocarcinoma, and 1 SD each in fallopian tube cancer, endometrium 
cancer, and parotid cancer. 
Please refer to the Investigators’ Brochure for detailed safety information. 
Rationale for the starting dose of ZW25 
Based on ZWI-ZW25-101, the recommended phase II dose of ZW25 was established at 
20mg/kg intravenously (IV) every two weeks. This established dose and schedule will be 
utilized in this study. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a MSKCC investigator-initiated, single-center, Phase 2, open label study 
designed to evaluate the efficacy and safety of ZW25, in patients with HER2 
overexpressing endometrial carcinomas and endometrial carcinosarcomas. 
HER2 overexpression is defined as 3+ by IHC (immunohistochemistry) or 2+ with gene 
amplification by FISH (HER2/CEP17 ratio ≥or HER2 amplified (fold change ≥ 2) on MSK 
IMPACT. 


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Abbreviations – IV: intravenous ORR: Overall response rate, PFS: Progression- 
free survival, OS: Overall survival, CBR: Clinical benefit rate, DOR: Duration of 
response 
 
4.2 
Intervention 
Up to 25 patients will be enrolled on this study and will receive the RP2D of ZW25 at 
20mg/kg intravenously (IV) every two weeks. 
The study will be conducted in two stages. Stage 1 will accrue 16 patients; if two or more 
responses are seen, study will proceed to Stage 2 which will accrue an additional 9 
patients. In this study the recommended ZW25 dose will be 20mg/kg intravenously (IV) 
every two weeks. Treatment cycles will be 28 days long. 
Patients will receive study treatment until disease progression, intolerable toxicity, 
elective withdrawal from the study, study completion, or study termination. Patients will 
continue to receive study treatment until they present with progressive disease (PD) per 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, develop 
unacceptable toxicity or withdraw consent, whichever comes first, or until the study is 
terminated. 
Tumor assessments, including radiological assessments by computerized tomography 
(CT) or magnetic resonance imaging (MRI) scans are performed at Screening and 


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subsequently every eight weeks for the first 24 weeks and then every twelve weeks until 
PD, death or initiation of subsequent anti-cancer therapy, whichever occurs first. 
Safety will be evaluated in this study through the monitoring of all serious and non- 
serious AEs, graded according to the current version of the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE v.5). 
5. 0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC 
ASSESSMENTS 
5.1 ZW25 
 
ZW25 is supplied by Zymeworks Inc. as a sterile, single-use, preservative-free, colorless 
to slightly yellow solution in a glass vial. The drug product solution is for IV 
administration. 
MSK will be cross-referencing Zymeworks, Inc.’s IND for ZW25. 
ZW25 Formulation 
Each vial contains a nominal fill volume of 20 mL (300 mg). The drug product is 
formulated at 15 mg/mL in 10 mM sodium acetate, 9% (w/v) sucrose, and 0.01% (w/w) 
polysorbate 20. The pH of the drug product is 4.6. The final container is a 50 mL USP 
Type I glass vial with a gray Flurotec coated plug and yellow flip-off top seal. 
Storage and Handling 
 
Vials containing ZW25 must be stored under refrigeration at 20°C (±5 °C). 
Please refer to the Pharmacy Manual for further details on storage and handling. Drug 
accountability procedures are also provided in the Pharmacy Manual. Refer to the 
protocol and relevant Pharmacy Manual for specific guidelines regarding the preparation 
and administration of ZW25. 
Upon completion of the study, all study drug dispatched to a site must be accounted for 
destroyed according to the pharmacy’s standard operation procedures (SOP). The 
pharmacy shall maintain accurate records of all study drugs that have been received, 
stored, dispensed, destroyed, and used. 
Drug accountability will be monitored regularly. 
Preparation 
Refer to the protocol and relevant Pharmacy Manual for specific guidelines regarding the 
preparation and administration of ZW25. 


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Administration 
ZW25 will be administered by IV infusion in 0.9% normal saline over 120 to 150 minutes. 
If for a particular patient the first 2 doses administered are well tolerated, the infusion 
duration for that patient 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 of 0.9% normal saline/hour (Example: If a dose of 
ZW25 is diluted into 250 mL bag of saline, the infusion should be administered over at 
least 60 minutes. If a dose of ZW25 is diluted into 500 mL bag, the infusion should be 
administered over at least 120 minutes.) The study drug dosage will be calculated based 
on patient weight at Screening. Dose will be recalculated only if there is a change in 
weight by 10% from the assessment at Cycle 1 Day 1. Please refer to the Pharmacy 
Manual for further instructions and or specific guidelines regarding the preparation and 
administration of ZW25. 
All patients should receive pre-medication as prophylaxis for infusion reaction as 
described in Required Therapy section of the protocol. 
Overdose 
Any overdose or incorrect administration of ZW25 should be noted on the Study Drug 
Administration Electronic Case Report Form (eCRF). Adverse events associated with an 
overdose or incorrect administration of ZW25 should be recorded accordingly on the 
eCRF. 
Required Therapy 
Prior to dosing with ZW25, all patients should receive prophylactic treatment for infusion 
reactions that consists of acetaminophen orally, diphenhydramine (or equivalent) orally 
or IV, and a corticosteroid 30 to 60 minutes prior to infusion of ZW25. The dosage of 
these pre-medications may be determined by local institutional practice; however, the 
drug supplier’s recommendations are acetaminophen 650 mg orally, diphenhydramine 
50 mg orally or IV, and hydrocortisone 100 mg IV or dexamethasone 10 mg IV. All 
premedication administered should be documented for each infusion. If a patient cannot 
tolerate one or more of the premedication, please contact the Principal Investigator to 
discuss alternatives. 
 
Permitted Therapy 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Inactivated influenza vaccinations 
 
Megestrol administered as an appetite stimulant 
 
Inhaled corticosteroids (e.g., budesonide) 


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 
Mineralocorticoids (e.g., fludrocortisone) 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
G-CSF (i.e., filgrastim or pegfilgrastim) treatment is permitted. The primary prophylaxis 
should be administered per the ASCO, EORTC, or ESMO guidelines or per local standard 
practice; namely, in patients who are ≥ 60 years of age and/or with comorbidities (Smith et 
al. 2006; Crawford et al. 2009; Aapro et al. 2011). 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated per local standard practice. 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), 
whether health authority−approved or experimental, are prohibited for various time 
periods prior to starting study treatment, depending on the agent and during study 
treatment until disease recurrence is documented and the patient has discontinued study 
treatment, except as outlined below or as described elsewhere in the protocol. 
 
Investigational therapy is prohibited during the study. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to initiation 
of study treatment, during study treatment, and for 5 months after the last dose of study 
treatment. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) 
are prohibited within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to 
initiation of study treatment and during study treatment. 
 
Concomitant use of herbal therapies is not allowed on protocol therapy. 
Concomitant Therapy and Additional Restrictions 
Concomitant therapy during the study includes any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 7 
days prior to initiation of study treatment to the treatment discontinuation visit. All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
Concomitant Medications and Procedures 
All concomitant medications and supportive therapy taken within 7 days of Cycle 1 day 1 
and through 30 days after last study treatment must be recorded on the appropriate 
eCRF. The identity of all medications, dosage, and route of administration, frequency, 
duration of administration, and indication for use will be recorded in the appropriate 
sections of the eCRF. 


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Antiemetic and antidiarrheal medications 
Antiemetic (e.g. 5-HT3 serotonin receptor antagonists such as palonosetron, granisetron 
or ondansetron) and antidiarrheal (e.g. loperamide) medications may be used at the 
discretion of the treating physician. 
Hematopoietic Growth Factors 
Patients receiving recombinant erythropoietin or darbepoietin-α prior to study start may 
continue to receive pre-treatment doses. 
 
The use of erythropoietic and granulocyte growth factors in accordance with ASCO 
guidelines may be implemented at the discretion of the treating physician after Cycle 1. 
Other Concomitant Medications 
Medications for the treatment of adverse events or cancer symptoms (e.g. packed red 
blood cells and pain medications), are allowed. Additionally, medications (not addressed 
above) used to treat underlying medical conditions at study entry, including anti-emetics 
and anti-diarrheal medications, will be allowed to continue. 
 
Study Treatment Compliance 
ZW25 supplied for the study may not be used for any purpose other than the study or 
administered other than as described in this protocol. 
ZW25 from two different drug lots cannot be mixed in a single dose administration. 
Study Treatment Administration 
ZW25 is an experimental anticancer drug, and, as with other potentially toxic 
compounds, caution should be exercised when handling these compounds. It is 
recommended that gloves and protective garments be worn during preparation. Refer to 
the Pharmacy Manual for more information. 
Study Treatment Overview and Schedule 
All Cycle visits are allowed a ± 3-day window (see study calendar for details). Note that 
there must be a minimum of 12 days between doses. If Day 1 of a cycle is delayed for 
any reason, once the subject reinitiates treatment the next dose delivered will be 
considered Day 1 of the cycle that was delayed. If a Day 15 dose of a cycle is delayed 
by ≥ 12 days, then that dose will be considered skipped. The next dose delivered will be 
considered Day 1 of the subsequent cycle. For logistical reasons such as holidays, 
delays in the scheduled study treatment please consult with PI. 
 
6.0 
CRITERIA FOR PARTICIPANT ELIGIBILITY 
6.1 
Participant Inclusion Criteria 
1. Patients must be enrolled or agree to consent to the companion genomic 
profiling study MSKCC IRB# 12-245 Part A. Results are not required prior to 


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initiating treatment on protocol, unless patients do not have other test results by 
IHC or FISH confirming HER2 overexpression. 
2. Patients must have recurrent or persistent HER2 overexpressing endometrial 
cancer or endometrial carcinosarcoma. HER2 overexpression is defined as 3+ 
by IHC or 2+ with gene amplification by FISH (HER2/CEP17 ratio ≥ 2) or HER2 
amplified (fold change ≥ 2) on MSK IMPACT. 
3. Histologic documentation of diagnosis of endometrial carcinoma or 
carcinosarcoma is required. 
4. Age ≥ 18 years 
5. Patients must have had at least one but no more than two prior 
chemotherapeutic regimens for management of endometrial carcinoma 
(including neo-adjuvant and/or adjuvant chemotherapy). Initial treatment may 
include chemotherapy, chemotherapy and radiation therapy, and/or 
consolidation/maintenance therapy. Chemotherapy administered in conjunction 
with primary radiation as a radio-sensitizer WILL be counted as a systemic 
chemotherapy regimen. Prior hormonal therapy will not count as a prior 
regimen. 
Prior treatment with trastuzumab is allowed. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
7. LVEF ≥ 50% on baseline screening ECHO. 
8. Resolution of adverse effects of recent surgery, radiotherapy, or chemotherapy 
to Grade ≤1 prior to first study treatment (with the exception of alopecia or 
clinically insignificant laboratory values). 
9. Patients must have measurable disease. Measurable disease is defined by 
RECIST (version 1.1). Measurable disease is defined as at least one lesion that 
can be accurately measured in at least one dimension (longest diameter to be 
recorded). Each non-nodal lesion must be  10 mm when measured by CT, 
MRI or caliper measurement by clinical exam; or  20 mm when measured by 
chest x-ray. Lymph nodes must be ≥ 15 mm in short axis when measured by 
CT or MRI. 
10. No active infection requiring antibiotics (with the exception of uncomplicated 
urinary tract infection). 
11. All patients must consent to mandatory pre-treatment and post-treatment core 
needle biopsies. 
12. Patients must have adequate hematological, liver, cardiac and kidney function 
within 14 days prior to first treatment: 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
b. Platelet ≥ 100 x 109/L (>100,000 per mm3) 
c. Hemoglobin ≥ 8.0 g/dL 


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d. Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). (Unless 
Gilbert’s Syndrome, for which Bilirubin ≤ 3 x institutional upper limit of 
normal (ULN), without concurrent clinically significant liver disease) AST 
(SGOT)/ALT (SGPT) ≤ 3 x institutional upper limit of normal (ULN) 
unless liver metastases are present, in which case it must be ≤ 5x ULN. 
e. Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN). 
13. For patients of childbearing potential, agreement to use two effective forms of 
contraception (e.g., surgical sterilization, a reliable barrier method, birth control 
pills, or contraceptive hormone implants) and to continue its use for the duration 
of the study and for 12 weeks after the last ZW25 dose. 
14. Agree to practice total abstinence when this is in line with the preferred and 
usual lifestyle of the subject. 
a. A woman is considered to be of childbearing potential unless 1 of the 
following applies: She is considered to be permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, tubal ligation, and bilateral oophorectomy. 
b. She is postmenopausal, defined as no menses for 12 months without an 
alternative medical cause. A high follicle-stimulating hormone (FSH) 
level consistently in the postmenopausal range (30 mIU/mL or higher) 
may be used to confirm a postmenopausal 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 to confirm a postmenopausal state. 
c. Female patients of childbearing potential must have a negative serum 
pregnancy test result less than 3 day prior to administration of the first 
dose of study treatment. 
Patients or their legally authorized representative (LAR) must be willing and able to sign 
the informed consent form, and to adhere to the study visit schedule and other protocol 
requirements. 
6.2 
Participant Exclusion Criteria 
1. Women who are pregnant or lactating or women of childbearing potential 
(WCBP) not protected by highly effective contraceptive methods. 
2. > Grade 1 peripheral neuropathy. 
3. History of hemorrhagic or ischemic stroke within the prior six months. 
4. History of NYHA Class II-IV heart failure, no serious arrhythmia. 
5. History of MI or unstable angina within 6 months of study initiation. 


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6. Patients with a lifetime cumulative dose of anthracycline >300 mg/m2 or who 
have received anthracycline treatment within 90 days of the expected first 
dose of ZW25 are not eligible for treatment. 
7. Prior hypersensitivity to monoclonal antibodies. 
8. Active hepatitis B or hepatitis C infection. Patients with previously resolved 
hepatitis B infection are eligible. Presence of positive test results for hepatitis 
B infection who have resolved the infection (defined by positive for HB surface 
antibody (anti-HBs) and polymerase chain reaction (PCR) assay is negative 
for HBV DNA are eligible. Patients positive for HCV antibody are eligible only if 
testing for HCV RNA is negative. 
9. Known HIV infection. 
10. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease). 
11. Major surgical procedure or significant traumatic injury within 28 days prior to 
Day 1 or anticipation of the need for major surgery during the course of study 
treatment. 
12. Known untreated or active central nervous system (CNS) metastases 
(progressing or requiring anticonvulsants or corticosteroids for symptomatic 
control) leptomeningeal carcinomatosis. 
Patients with a history of treated CNS metastases are eligible, provided that they 
meet all of the following criteria: 
a. Presence of measurable disease outside the CNS 
b. No radiographic evidence of worsening upon the completion of CNS- 
directed therapy and no evidence of interim progression between the 
completion of CNS-directed therapy and the screening radiographic 
study 
c. No history of intracranial hemorrhage or spinal cord hemorrhage 
d. No ongoing requirement for dexamethasone as therapy for CNS 
disease (anticonvulsants at a stable dose are allowed) 
e. Absence of leptomeningeal disease 
13. Inability to comply with study and follow-up procedures. 
14. Known allergy or hypersensitivity to the components of ZW25 formulation. 
15. Any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding that, in the investigator’s opinion, gives reasonable 
suspicion of a disease or condition that contraindicates the use of an 


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IRB Number: 20-162 A(7) 
Approval date: 07-Feb-2023 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 26 of 66
 
 
investigational drug or that may affect the interpretation of the results or render 
the patient at high risk from treatment complications. 
16. Active or history of inflammatory bowel disease (IBD) 
17. Severe infections within 4 weeks prior to initiation of study drug treatment, 
including but not limited to hospitalization for complications of infection, 
bacteremia, or severe pneumonia. 
18. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to 
initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., for 
prevention of urinary tract infection or to prevent chronic obstructive 
pulmonary disease exacerbation) are eligible for the study. Patients receiving 
antibiotic treatment for urinary tract infection are also eligible. 
19. Administration of a live attenuated vaccine within 4 weeks prior to initiation of 
study treatment or anticipated need for such a vaccine during study. Patients 
must agree not to receive live, attenuated influenza vaccine (e.g., Flumist®) 
within 4 weeks prior to treatment.) 
20. Participation in another clinical study with receipt of an investigational product 
during the last 4 weeks. 
21. History of another primary malignancy except for: 
a. Malignancy treated with curative intent and with no known active 
disease ≥2 years before the first dose of study drug and of low 
potential risk for recurrence. 
b. Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease. 
c. Adequately treated carcinoma in situ without evidence of disease (e.g., 
cervical cancer in situ). 
d. Adequately treated stage 1 breast cancer. 
22. Receipt of the last dose of anti-cancer therapy (chemotherapy, 
immunotherapy, targeted therapy, biologic therapy, tumor embolization, 
monoclonal antibodies) < 21 days prior to the first dose of study drug. Receipt 
of the last dose of hormonal therapy within < 7 days prior to the first dose of 
study drug. 
23. Any prior radiation therapy must be discontinued at least four weeks prior to 
registration. 
24. QT interval corrected for heart rate (QTc) ≥470 ms on screening 
electrocardiograms (ECG) using QTC Federica. 


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IRB Number: 20-162 A(7) 
Approval date: 07-Feb-2023 
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New York, New York 10065 
Page 27 of 66
 
 
25. History of small or large bowel obstruction within 3 months of registration, 
including subjects with palliative gastric drainage catheters. Subjects with 
palliative diverting ileostomy or colostomy are allowed if they have been 
symptom free for more than 3 months. 
26. Subjects with refractory ascites, defined as ascites needing drainage catheter 
or therapeutic paracentesis more often than every 4 weeks. 
27. Ongoing bowel perforation or presence of bowel fistula or abscess within 3 
months of registration. 
 
7.0 
RECRUITMENT PLAN 
All eligible patients, regardless of race, will be approached for participation. No additional 
measures, e.g. advertisement, payment to patients, will be employed to recruit patients. 
During the initial conversation between the investigator/research staff and the patient, 
the patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review 
portions of their medical records at MSKCC in order to further assess eligibility. They 
will use the information provided by the patient and/or medical record to confirm that the 
patient is eligible and to contact the patient regarding study enrollment. If the patient 
turns out to be ineligible for the research study, the research staff will destroy all 
information collected on the patient during the initial conversation and medical records 
review. 
 
Participation in the study is completely voluntary. Patients/LAR will be required to read, 
agree to, and sign an IRB-approved informed consent form prior to registration on this 
trial. Patients will not receive payment for their participation on this study. Patients are 
free to withdraw from the study without consequence at any time. 
 
Potential research subjects will be identified by a member of the patient’s treatment 
team, the protocol investigator, or research team at Memorial Sloan-Kettering Cancer 
Center (MSKCC). If the investigator is a member of the treatment team, s/he will screen 
their patient’s medical records for suitable research study participants and discuss the 
study and their potential for enrolling in the research study. Potential subjects contacted 
by their treating physician will be referred to the investigator/research staff of the study. 
Assignment of Patient Number 
Patient numbers are assigned in sequential order as patients patient enrolls onto study. 
 
The Investigator will certify that the patient satisfies all eligibility criteria at screening and 
continues to satisfy all inclusion and exclusion criteria on Cycle 1, Day 1 prior to dosing. 


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IRB Number: 20-162 A(7) 
Approval date: 07-Feb-2023 
Memorial Sloan Kettering Cancer Center 
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New York, New York 10065 
Page 28 of 66
 
 
Enrolled Patient Definition 
Patients who have consented to the study and have received at least one dose of study 
treatment will be considered enrolled and evaluable. Those patients who’ve consented 
but did not successfully complete the screening process and did not receive a dose of 
ZW25 will be considered a screen failure. Patient numbers for patients who screen fail 
will not be re-issued. 
7.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility 
Checklist is confirming whether the participant is eligible to enroll in the study. Study staff 
are responsible for ensuring that all institutional requirements necessary to enroll a 
participant to the study have been completed. See related Clinical Research Policy and 
Procedure #401 (Protocol Participant Registration). 
 
8.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants or their LARs must 
sign an IRB/PB-approved consent form indicating their consent to participate. This 
consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include 
the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 


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IRB Number: 20-162 A(7) 
Approval date: 07-Feb-2023 
Memorial Sloan Kettering Cancer Center 
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New York, New York 10065 
Page 29 of 66
 
 
Each participant or their LAR and consenting professional will sign the consent form. 
The participant must receive a copy of the signed informed consent form. 
 
9.0 
PRE-TREATMENT/INTERVENTION 
Screening Visit 
In some cases, clinical assessments performed prior to obtaining informed consent may 
be used to qualify the patient for the study. These include radiological tumor 
assessment, physical examinations, hematology, serum chemistry results, coagulation 
studies, urinalysis, or other assessments which may be considered part of normal 
standard of care. In these cases, repeat assessments may not be necessary prior to 
enrollment, unless individual parameters require further study or confirmation and are 
clinically appropriate. 
 
Within 28 days prior to treatment start: 
• 
Written informed consent 
• 
History and Physical examination 
• 
Review of concomitant medications 
• 
Vital signs (blood pressure, heart rate and temperature), weight and height 
• 
ECOG Performance status 
• 
Toxicity assessment 
• 
12-lead ECG 
• 
Echocardiogram 
• 
Radiographic tumor measurements (CT C/A/P, MRI) 
• 
Screening Biopsy (3 Cores) if deemed safe and feasible (Refer to: Exploratory 
Correlative Studies section for details) 
• 
Patients must have documented HER2 overexpression, defined as 3+ by IHC or 2+ with 
gene amplification by FISH (HER2/CEP17 ratio ≥ 2) or HER2 amplified (fold change ≥ 2) 
on MSK IMPACT any time prior to starting treatment 
• 
Hepatitis B Testing, if not done previously at MSK to rule out active infection (see 
exclusion criteria for details) 
 
Within 14 days prior to treatment start: 
 
Complete Blood Count (CBC) with differential 
 
Comprehensive profile (BUN, creatinine, sodium, potassium, chloride, CO2, calcium, 
glucose, total bilirubin, total protein, albumin, alkaline phosphatase, AST, ALT) 
 
Coagulation tests: Prothrombin time, APTT and INR (PT/PTT) 
 
Magnesium 
 
Uric Acid 
 
Urinalysis 
 
Pregnancy test (in women of childbearing potential) 
o Women of child bearing potential (WCBP), defined as a sexually mature woman who 
has not undergone surgical sterilization or who has not been naturally 
postmenopausal for at least 12 consecutive months (i.e., who has had menses any 
time in the preceding 12 consecutive months) must agree to use effective 


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IRB Number: 20-162 A(7) 
Approval date: 07-Feb-2023 
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New York, New York 10065 
Page 30 of 66
 
 
contraceptive methods. Acceptable single methods include intrauterine device, 
vasectomy of a female patient’s male partner, and contraceptive rod implanted into 
the skin. Abstinence (relative to heterosexual activity) can be used as the sole 
method of contraception if it is consistently employed as the patient’s preferred and 
usual lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs. Periodic abstinence (e.g., ca, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
Acceptable combination methods (requiring use of two of the following) are 
acceptable: diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide), cervical cap with spermicide (nulliparous women only), 
contraceptive sponge (nulliparous women only), male condom or female condom 
(cannot be used together), or hormonal contraceptive such as oral contraceptive pill, 
estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal 
contraceptive ring, or subcutaneous contraceptive injection. Acceptable methods of 
contraception must be used while on study treatment and for at least twelve weeks 
after the last dose of ZW25. 
o All female patients of child-bearing potential will complete a serum beta-human 
chorionic gonadotropin (β-hCG) or urine pregnancy test (not more than 3 days 
before the first dose of ZW25); this test must be negative for the patient to be 
enrolled and to receive the study drug. 
 
ECGs are required during screening, on Cycle 1 Day 1 and Cycle 3 Day 1. 
Vital signs will be evaluated according to the Schedule of Assessments listed on section 11 
of the protocol. 
 
 
10.0 
TREATMENT/INTERVENTION PLAN 
Study treatment will begin on Day 1 of each 4 week dosing cycle (28 days). 
 
In this study the recommended ZW25 dose will be 20mg/kg intravenously (IV) every two 
weeks on Days 1 and Days 15 a 28-day cycle. 
Patients will continue to receive study treatment until they present with progressive 
disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, 
develop unacceptable toxicity or withdraw consent, whichever comes first, or until the 
study is terminated. 
Tumor assessments, including radiological assessments by computerized tomography 
(CT) or magnetic resonance imaging (MRI) scans are performed at Screening and 
subsequently every eight weeks for the first 24 weeks and then every twelve weeks until 
progression of disease, death or initiation of subsequent anti-cancer therapy, whichever 
occurs first. 
Pre- and post-treatment fresh tumor biopsies, blood and serum samples will be collected 
for biomarker analysis. Post-treatment tumor biopsy will only be performed upon 


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Page 31 of 66
 
 
progression of disease. Results from tissue testing will not be returned to patients. (See 
Exploratory Correlative Studies section for details) 
End of Treatment and Follow-up 
End of Treatment Visit 
Patients may voluntarily withdraw from the study treatment at any time for any reason, 
and without prejudice to further treatment. In addition, patients may be withdrawn by the 
Investigator if they do not feel the patient is deriving clinical benefit or because the 
patient is experiencing unacceptable toxicity. The reasons for which a patient may be 
removed from study are listed in Section 12. 
 
Patients who withdraw or is removed from study treatment will have an end of treatment 
visit within 7 days of the decision to discontinue study treatment. Additionally, these 
patients will undergo a 30-day follow-up safety visit. The eCRF will capture reasons for 
withdrawal. 
30-Day Safety Follow-up 
A safety follow-up visit will occur 30 days (+14 days) after the last treatment. 
All serious adverse events, and those adverse events assessed by the Investigator as at 
least possibly related to study drug should continue to be followed until they resolve or 
stabilize, whichever comes first. Reporting of SAEs are detailed in Section 15.1. 
Survival Follow-up 
All patients who discontinue study treatment for any reason will be proceed onto survival 
follow up. Patients will be followed up for survival status every 3 months (from End of 
treatment visit) for 2 years until death, lost to follow up or withdrawal of consent. 
Exploratory Correlative Studies 
1. Anti-drug antibodies (ADA) will be assessed at baseline (baseline ADA can be collected 
on C1D1 pre dose) and pre-dose at Cycles 2, 4, 6, 8, 12, 18, 24 Day 1. The 
immunogenicity testing will be performed using validated assays 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 further titrated to 
determine the titer of ADA. 
At each timepoint, 5mL of blood will be collected into a red top tube and processed as 
follows: 
 
Invert 5x 
 
Clot at least for 30 minutes 
 
Separate serum within 30-60 minutes of collection 
 
Centrifuge 1000-2000 x g at 4c for 15-20min 
 
~1.25mk serum into each 2ml cryovial 
Storage: Store at -70o F/-80oF (storage at -20o F acceptable) for up to 1 month. Ship 
frozen on dry ice monthly. Blood samples for ADA will be processed and stored at the 
Immune Monitoring Facility (IMF) until batch shipment to Zymeworks, Inc. 


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IRB Number: 20-162 A(7) 
Approval date: 07-Feb-2023 
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New York, New York 10065 
Page 32 of 66
 
 
2. To explore the molecular associations between the HER2 biomarkers: gene 
amplification (by NGS and ISH), protein overexpression by immunohistochemistry (IHC) 
and mutational status and/or copy # variations of relevant cancer-related genes using 
MSK-IMPACT platform in all patients and to determine mechanisms of underlying 
response and resistance. 
3. Mandatory pre-treatment and post-treatment tumor biopsies will be obtained on all 
patients to assess HER2 expression, its association with treatment response and other 
genetic changes over time. Attempts will be made to collect 3 cores (Flash Frozen) of 
tumor material at each time point for research purposes under the current study. 
Biopsies will only be performed if deemed safe and feasible by the investigator. Post- 
treatment biopsy will only be done upon progression of disease. Tissue testing will be 
performed in the CMO. To determine mutational status and/or copy number variations of 
relevant cancer related genes using MSK-IMPACT platform in patients with response to 
therapy. MSK-IMPACT tests will be done on new biopsy specimens for research 
purposes in the context of this protocol. Results from these testing will not be reported to 
patients. 
4. To determine the ability of the laboratory parameters to predict clinical benefit: 
a. All patients will undergo mandatory pre-treatment fresh tumor biopsy (if deemed 
clinically safe). Post-treatment fresh tumor biopsy will be done upon disease 
progression. 
5. To evaluate the predictive value of changes in circulating tumor DNA variant allele 
frequency during treatment for response to ZW25. Circulating plasma cell-free DNA will 
be collected at pre-treatment (any time prior to C1D1), and at End of Treatment. MSK’s 
standard cfDNA workflow will be followed (one streck tube). 
a. Liquid biopsy through the sequencing of plasma ctDNA has the potential to 
address multiple biologic questions, including global tumor heterogeneity. 
Targeted deep sequencing of candidate driver oncogenes facilitates analysis of 
the clonal structure of the tumor, and prioritization of clinically relevant actionable 
targets. As blood content theoretically integrates mutational data from all sites of 
disease, deep analysis of plasma ctDNA may offer a solution to the problem of 
assessing intratumoral heterogeneity with tumor biopsies, and ultimately could 
define a systemic genomic approach to guide application of targeted therapies. A 
novel bioinformatics algorithm called FACETS developed at Memorial Sloan 
Kettering will be applied to interrogate clonality from targeted sequencing of 
ctDNA. 
 
Whole genome or whole exome sequencing will not be done in this study unless activity 
is seen after data review, at which point the protocol may be amended to include 
additional objectives. 
 
Incidental Inherited Genomic Findings: 
In the course of this research it is possible that some patients whose tumors are 
analyzed through investigational “next-generation” profiling in a research (non-CLIA) 
environment will be found to have somatic or germline mutations in genes that are 
known to be associated with an increased risk of cancer or other diseases. It will be 
stated in the consent that the participants will not receive any specific results from 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-162 A(7) 
Approval date: 07-Feb-2023 
Memorial Sloan Kettering Cancer Center 
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Page 33 of 66
 
 
research tests. The consent will tell participants that if they wish to have genetic testing 
done for personal reasons than they should make an appointment with the MSK Clinical 
Genetics Service. 
If in the course of this research a research finding is obtained that, in the opinion of the 
investigator, may be critical to the preventive care of the participant or their family, the 
investigator can communicate that finding to the IRB Genomic Advisory Panel (GAP). 
The finding will be reviewed by the GAP to determine whether the incidental finding 
should be discussed with the participant. For MSK, in the event that the GAP determines 
that the finding should be discussed with the participant, and the participant has 
consented to be re-contacted, then the treating/consenting physician shall be contacted 
by the panel and asked to refer the participant to the Clinical Genetics Service for further 
discussion of the research finding. 
The following information must be provided to GAP for review: 
• Participant Name/MRN # 
• Type of Biospecimen (tissue, blood, saliva) 
• Incidental Finding 
• Collection Protocol # 
• Contact: rtmgapirb@mskcc.org 
 
6. Early changes in clonal variant allele frequency of HER2 may serve as a powerful 
predictor of response to targeted therapy. We hypothesize that plasma ctDNA can be 
used as a non-invasive early predictive biomarker to distinguish between responders 
and non-responders to targeted therapy, refining precision medicine. Clonal changes of 
actionable drivers and the emergence of new somatic genetic alterations through serial 
ctDNA sequencing should offer novel insights into understanding and overcoming drug 
resistance driven by Darwinian clonal evolution. This may be paradigm changing in the 
way we select therapy to treat patients and fundamentally change future clinical trials 
design. 
7. To examine ORR in each cohort by different types of molecular alterations, HER2 
amplification (by NGS and ISH separately), mutation and HER2 overexpression, and 
assess their predictive value for response. 


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IRB Number: 20-162 A(7) 
Approval date: 07-Feb-2023 
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Page 34 of 66
 
 
 
 
11.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
 
 
 
Activity 
 
 
 
Screening 
 
Cycle 1 
(± 3 days) 
 
Cycle 2 
(± 3 days) 
 
Cycle 3 
(± 3 days) 
 
Cycles 4+ 
(± 3 days) 
 
End of 
Treatment 
(within 7 days
of decision to 
discontinue 
Treatment) 
 
30-Day 
Follow- 
up 
(+ 14 
Days) 
 
Survival 
Follow- 
up 
(+14 
days) 
Day 1 
Day15 
Day 1 
Day15 
Day 1 
Day15 
Day 1 
Day15 
Informed 
consent 
●a 
 
 
 
 
 
 
 
 
 
 
 
Demography 
●a 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
●a 
 
 
 
 
 
 
 
 
 
 
 
Confirm 
Disease 
Diagnosis from 
fresh biopsy 
 
 
●a 
 
 
 
 
 
 
 
 
 
 
 
Record 
Baseline Signs 
and Symptoms 
 
●a 
 
● 
 
 
 
 
 
 
 
 
 
 
Review and 
document 
IC/EC 
 
●a 
 
 
 
 
 
 
 
 
 
 
 
Confirm 
patient 
continues to 
satisfy I/E 
Criteria 
 
 
● 
 
 
 
 
 
 
 
 
 
 
Height 
●a 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examinationb 
●a 
● 
● 
● 
● 
● 
 
● 
 
● 
● 
 
Weight 
●a 
● 
 
● 
 
● 
 
● 
 
● 
● 
 
Vital signsd 
●a 
● 
● 
● 
● 
● 
 
● 
 
● 
● 
 
ECOG PS 
●a 
●j 
 
● 
 
● 
 
● 
 
● 
● 
 
Hematology 
and 
Chemistry e 
 
 
●c 
 
● 
 
● 
 
● 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 


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IRB Number: 20-162 A(7) 
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New York, New York 10065 
Page 35 of 66
 
 
 
 
 
 
Activity 
 
 
 
Screening 
 
Cycle 1 
(± 3 days) 
 
Cycle 2 
(± 3 days) 
 
Cycle 3 
(± 3 days) 
 
Cycles 4+ 
(± 3 days) 
 
End of 
Treatment 
(within 7 days
of decision to 
discontinue 
Treatment) 
 
30-Day 
Follow- 
up 
(+ 14 
Days) 
 
Survival 
Follow- 
up 
(+14 
days) 
Day 1 
Day15 
Day 1 
Day15 
Day 1 
Day15 
Day 1 
Day15 
 
Magnesiume 
 
 
●a 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
● 
 
Coagulation 
(PT/INR/ 
aPTT) e 
 
●c 
 
 
 
 
 
● 
 
 
 
 
● 
 
 
 
cfDNA o 
 
 
●o 
 
 
 
 
 
 
 
 
 
 
●o 
 
 
Hepatitis B 
surface 
antigen p 
 
●a 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B 
Core Ab 
(total) p 
 
● a,h 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C 
antibody h 
● a,h 
 
 
 
 
 
 
 
 
 
 
 
Urinalysise, f 
●c 
● 
 
● 
 
● 
 
● 
 
 
● 
 
Uric Acid 
●c 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(urine or 
Serum)f 
 
●c 
 
●f 
 
 
●f 
 
 
●f 
 
 
●f 
 
 
 
●f 
 
Radiologic 
tumor 
assessments g 
 
●a 
 
 
Every 8 weeks (from C1D1) until Week 24, then 
every 12 weeks (± 1 week)g 
 
●h 
 
●h 
 
12-Lead ECG 
●a 
● 
 
 
 
● 
 
 
 
● 
● 
 
ECHO 
● 
Every 12 weeks (from C1D1) 
● 
 
 
ZW25 
Administration 
 
● 
 
● 
● 
● 
● 
● 
● 
● 
 
 
 
AE and SAE 
assessmentsi 
● k,i 
● i 
● i 
● i 
● i 
● i 
● i 
● i 
● i 
● i 
● i 
 
Record 
concomitant 
medications 
 
●a 
 
● 
 
● 
 
● 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 
Research blood 
collectionm 
 
●m 
 
●m 
 
● 
 
 
 
 
● m 
 
 
 
 


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IRB Number: 20-162 A(7) 
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Page 36 of 66
 
 
 
 
 
 
Activity 
 
 
 
Screening 
 
Cycle 1 
(± 3 days) 
 
Cycle 2 
(± 3 days) 
 
Cycle 3 
(± 3 days) 
 
Cycles 4+ 
(± 3 days) 
 
End of 
Treatment 
(within 7 days
of decision to 
discontinue 
Treatment) 
 
30-Day 
Follow- 
up 
(+ 14 
Days) 
 
Survival 
Follow- 
up 
(+14 
days) 
Day 1 
Day15 
Day 1 
Day15 
Day 1 
Day15 
Day 1 
Day15 
 
Mandatory 
biopsyn 
 
 
● 
 
 
 
 
 
 
 
 
● 
only upon 
disease 
progressio
n 
 
 
Survival 
Status n 
 
 
 
 
 
 
 
 
 
 
 
 
● n 
a. Within 28 days prior to the start of Cycle 1, Day 1 
b. Directed physical examination is acceptable while on study treatment. Full examination is required at 
screening and the EOT visit. 
c. Within 14 days prior to the start of Cycle 1, Day 1 
d. Vital signs (blood pressure, pulse, respiration rate, and temperature) will be measured as outlined in 
the full protocol. 
e. Day 1 laboratory assessments may be performed up to 4 days prior to study agent administration. 
Laboratory results must be reviewed prior to each scheduled administration of ZW25, with the 
exception of coagulation testing (PT/INR, aPTT). In the event of severe toxicity, laboratory tests must 
be repeated as necessary until the toxicity resolves or stabilizes. 
f. 
For WCBP, a urine or serum pregnancy test will be performed at screening, prior to dosing on Day 1 
of every cycle (it can be performed up to 14 days prior to Day 1) and at the 30-day Follow-Up visit. 
Additional testing may be performed in accordance with institutional requirements or local regulation. 
g. Patients will complete tumor assessments every 8 weeks (from C1D1) until Week 24, then every 12 
weeks (± 1 week). If a patient discontinues prior to documentation of PD, a tumor assessment is to be 
performed at the End of Study visit or 30-Day Follow up visit, if not performed within the previous 6 
weeks. Patients who have discontinued study treatment for reasons other than PD will be followed 
per RECIST 1.1 every 12 weeks (±3 weeks) until documentation of PD, starting a subsequent anti- 
cancer therapy or for up to one year from Cycle 1, Day 1, whichever comes first. 
h. As clinically indicated. 
i. 
All AEs and SAEs from the time of informed consent should be recorded. 
j. 
ECOG assessment is not necessary on Cycle 1 Day 1 if screening assessment was performed within 
3 days prior 
k. For logistical reasons such as holidays, a +/- 3 day window applies to all study visits. 
l. 
Mandatory biopsy at screening and EOT (at time of progression of disease) within 14 days of EOT 
before initiating new treatment regimen. 
m. Research bloods include ADA and cfDNA sample collection. Research bloods can be collected at 
screening or cycle 1 day 1 before initiating treatment for baseline collections. 
ADA will be collected at baseline and pre-dose at cycles 2, 4, 6, 8, 12, 18, 24 Day 1. 
n. Survival status’ can be documented with a phone call or any clinic visits. 
o. CfDNA will be collected at screening or cycle 1 day 1 before initiating treatment for baseline 
collections and again at End of Treatment 
p. 
Hepatitis B Testing, if not done previously at MSK to rule out active infection (see exclusion criteria for 
details) 


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12.0 
CRITERIA FOR REMOVAL FROM STUDY 
Discontinuation of Study Treatment Due to Adverse Events 
If ZW25 is discontinued, the patient must be discontinued from the study. Study 
treatment should not be resumed in the case of the following treatment-related events. 
 
≥ Grade 3 cardiac event 
 
Other non-hematologic events of Grade 4 severity 
 
Failure to meet re-treatment criteria within one cycle due to insufficient recovery from 
a treatment-related toxicity. In such cases, continuation of study treatment may be 
considered for those patients who have experienced clinical benefit if agreed upon 
by the Principal Investigator. 
 
Removal of the Patient from the Study or from Study Drug Administration 
The patient or legally authorized representative is free to withdraw consent and 
discontinue participation in the study at any time without prejudice to further treatment. 
 
Patients will be removed from the study treatment when their disease worsens, and 
there is no clinical benefit. Additionally, a patient’s participation in the study may be 
discontinued at any time at the discretion of the Investigator. The following may be 
justifiable reasons for the Investigator to remove a patient from the study: 
 
The patient suffers an intolerable adverse event 
 
Non-compliance, including failure to appear at one or more study visits 
 
The patient was erroneously included in the study 
 
The study is terminated. 
If a patient or the patient’s legal guardian(s), acting on behalf of the patient, discontinues 
participation in the study, or the patient is discontinued by the Investigator, the reason for 
discontinuation must be captured in the eCRF. Any AEs experienced up to the point of 
discontinuation must be documented on the AE eCRF. All serious adverse events 
(SAEs), and those AEs assessed by the Investigator as at least possibly related to study 
drug should continue to be followed until they resolve or stabilize, whichever comes first. 
 
 
13.0 
CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY 
13.1 Criteria for Therapeutic Response/Outcome Assessment 
RESPONSE DEFINITION (RECIST 1.1)48 
DEFINITIONS: 
Baseline: Baseline is defined as the most recent assessment performed prior to the 
first dose of study treatment. Baseline assessments must be performed within the period 
defined in the protocol eligibility criteria. 


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Measurable Lesions: Except for lymph nodes (described below), measurable lesions 
are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as ≥ 10 mm with CT scan (if CT scans have slice thickness 
greater than 5 mm, the minimum size of a measurable lesion is twice the slice 
thickness). 
 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be 
measured and recorded. 
 
MRI may be substituted for contrast-enhanced CT for lesions at some anatomical sites, 
but not for lesions in the lungs. The minimum size for measurability is the same as for 
CT (10 mm) as long as the scans are performed with slice thickness of 5 mm and no 
gap. If MRI is performed with thicker slices, the size of a measurable lesion at baseline 
should be twice the slice thickness. In the event there are inter-slice gaps, this also 
needs to be considered in determining the size of measurable lesions at baseline. 
Non-measurable lesion: all other lesions (or sites of disease) including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis), 
are considered non-measurable. 
 
Lymph nodes that have a short axis < 10mm are considered non-pathological and are 
not to be recorded or followed. 
 
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Target lesions: 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, are to be identified as target lesions and measured 
and recorded at baseline. 
 
Target lesions are to be selected on the basis of their size (lesions with the longest 
diameter) to represent all involved organs, and to be those that lend themselves to 
reproducible repeated measurements. 
 
It may be the case that on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. 


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 
Target lesions will be measured at each assessment (longest axis for non-nodal lesions, 
shortest axis for measurable malignant nodal lesions). 
Non-target lesions: All other lesions (or sites of disease) including all non-measurable 
lesions (including pathological lymph nodes with ≥ 10 to < 15 mm short axis) and all 
measurable lesions over and above the 5 target lesions are to be identified as non-target 
lesions and recorded at baseline. 
 
Measurements of these lesions are not required, but the presence, absence, 
unequivocal progression of each is to be recorded throughout follow-up. 
 
Lymph nodes that have a short axis < 10 mm are considered non-pathological and 
are not to be recorded or followed. 
Special Considerations 
Clinical Examination of Lesions: Superficial or visible lesions that cannot be assessed 
by CT scan or MRI will only be considered for response assessment if these lesions are 
biopsy-proven metastatic lesions and ≥ 10 mm in diameter. These lesions will be 
considered non-measurable and thus non-target for response assessment. 
Cystic lesions: Cystic lesions thought to represent cystic metastases can be considered 
as measurable lesions if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesion. 
Bone lesions: Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to confirm 
the presence or disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
 
Blastic bone lesions are non-measurable. 
Lesions with prior local treatment: Lesions situated in a previously irradiated area, or 
in an area subjected to other locoregional therapy, are usually not considered 
measurable; however, if they meet the following criteria, they may be considered for 
study: 
 
there has been prior documented progression in the lesion by at least 2 sequential 
CT or MRI scans performed after the completion of radiation, or 


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 
histopathological evidence of progression 
Additionally, if such lesions meet the criteria for measurability, they may be considered 
target lesions. 
Imaging Methods: 
The same method of assessment and the same technique used to characterize each 
identified and reported lesion at baseline should be used during each follow-up 
assessment. Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam (referring to biopsy-proven visible lesions(s) at the vaginal apex). 
Chest X-ray: Lesions that are identified on chest X-ray must be confirmed and followed 
by CT scan. If there is/are pre-existing chest lesion(s) before the baseline tumor 
assessment, a chest X-ray is not necessary to assess those lesions. The pre-existing 
chest lesion(s) must be assessed at baseline and followed by CT scans. 
Conventional CT or MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion is twice the slice 
thickness. MRI is also acceptable in certain situations (e.g., for body scan) except for 
lung. 
Other methods of assessment, PET-CT, ultrasound and FDG-PET should not be used 
for response assessment in this study. 
Time Point Assessments: 
Patients will have tumor measurements performed within 28 days prior to baseline and 
every 8 weeks through Week 24 and then every 12 weeks after 24 weeks, per RECIST 
1.1 guidelines. 
At baseline, tumors and lymph nodes are classified and documented as target or non- 
target per the definitions provided above. It is possible to record multiple non-target 
lesions involving the same organ as a single item (e.g., ‘multiple liver metastases’). 
At all post-baseline evaluations, the baseline classification (target, non-target) is to be 
maintained and lesions are to be documented and described in a consistent fashion over 
time (e.g., recorded in the same order on source documents and CRFs). 
For target lesions, measurements should be taken and recorded in metric notation. All 
tumor measurements must be recorded in millimeters. 


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At each assessment, a sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and reported. The baseline sum 
of the longest diameters (SLD) will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. The lowest SLD 
(nadir) since, and including, the baseline value will be used as reference for evaluating 
progression. 
After baseline, the actual size of the target lesion should be documented, if possible, 
even if the lesions become very small. If in the opinion of the radiologist, the lesion has 
likely disappeared, 0 mm should be recorded. If the lesion is present but too small to 
measure, an indicator of “too small to measure” will be provided on the CRF (a default 
value of 5 mm will be imputed during analysis). 
Non-target lesions are to be assessed qualitatively (present, resolved, or unequivocal 
progression) and new lesion, if any, are to be documented separately. 
At each evaluation, a time point response is to be determined for target lesions, non- 
target lesions, new lesions and overall. 
Time Point Response Criteria 
 
Target Lesion Time Point Response (TPR)
Complete Response (CR) 
Disappearance of all target lesions. All pathological lymph nodes 
(whether target or non-target) must have reduction in short axis 
to < 10 mm. 
Partial Response (PR) 
At least 30% decrease in the SoD of target lesions, taking as 
reference the baseline SoD 
Progressive Disease (PD) 
At least a 20% increase in the SoD of target lesions, taking as 
reference the smallest (nadir) SoD since and including baseline. 
In addition to the relative increase of 20%, the SoD must also 
demonstrate an absolute increase of at least 5 mm. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 
Not Applicable (N/A) 
No target lesions identified at baseline 


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Unable to Evaluate (UE) 
One or more target lesions are not imaged and the remainder of 
the SoD compared with the nadir SoD does not meet the criteria 
for PD 
If the target lesion for a patient meets the criteria for both PR and PD at a given time point, 
the target lesion response is PD. 
If the nadir SoD is 0 (i.e., the patient had a prior target lesion CR), the re-appearance of any 
prior target lesions to any degree constitutes PD. 
Non-Target Lesion TPR
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of 
tumor marker level if tumor marker at baseline is above the upper 
normal limit. All lymph nodes must be non-pathological in size (< 
10 mm short axis) 
Progressive Disease (PD) 
Unequivocal progression of non-target lesions. Unequivocal 
progression should not normally trump target lesion status. It 
must be representative of overall disease status change, not a 
single lesion increase. 
Not Applicable (N/A) 
No non-target lesions identified at baseline 
Unable to Evaluate (UE) 
One or more non-target lesions are not imaged and the 
remaining non-target lesions do not meet the criteria for PD 
If the target lesion for a patient meets the criteria for both PR and PD at a given time point, 
the target lesion response is PD. 
If the nadir SoD is 0 (i.e., the patient had a prior target lesion CR), the re-appearance of any 
prior target lesions to any degree constitutes PD. 
 
 
New Lesion TPR 
Yes 
Lesion present at follow-up visit either for the very first time or re- 
appearing (i.e., lesion was present at baseline, disappeared at a 
follow-up visit and re-appeared later). 
No 
No new lesions present at follow up 


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Unable to Evaluate (UE) 
Patient non-assessed or incompletely assessed for new lesion 
Determining Overall TPR 
 
Target Lesion TPR 
Non-Target TPR 
New Lesions TPR 
Overall TPR 
CR 
CR or NA 
No 
CR* 
CR 
Non-CR/non-PD 
No 
PR* 
CR 
UE 
No 
PR* 
PR 
Non-PD or NA or UE 
No 
PR* 
SD 
Non-PD or NA or UE 
No 
SD 
UE 
Non-PD 
No 
UE 
PD 
Any 
No or Yes or UE 
PD 
Any 
PD 
No or Yes or UE 
PD 
Any 
Any 
Yes 
PD 
NA 
CR 
No 
CR* 
NA 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Non-PD 
Non-PD 
UE 
UE 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; 
UE, unable to evaluate; NA, not applicable (no such lesions at screening); Any, CR, PR, SD, 
PD, NA or UE. 
The overall response at a given time point does not depend upon the overall response 
assigned at any prior time point. 
*Patients with an overall response of CR or PR must have a repeat tumor assessment 
performed no less than 4 weeks after the criteria for response are first met 
Confirmation - The main goal of confirmation of objective response is to avoid 
overestimating the observed response rate. For patients with an overall response of PR 
or CR a given time point, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. However, the presence or absence of confirmation is not 
considered when assigning a time point response. 


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Best Overall Response - Best overall response, incorporating confirmation 
requirements, will be derived during statistical analysis from the series of time point 
responses and need not be considered when assigning response at any time point. 
 
13.2 Criteria for Study Endpoint Evaluability 
Patients who have consented to the study and who have received at least one dose of 
study treatment will be considered enrolled and evaluable. Those patients who’ve 
consented but did not successfully complete the screening process and did not receive a 
dose of ZW25 will be considered a screen failure. Patient numbers for patients who 
screen fail will not be re-issued. 
 
14.0 
BIOSTATISTICS 
14.1 Populations for Analyses 
 
All treated population: all treated patients regardless if they completed cycle 1 or the 
amount of drug received. 
 
Efficacy population: All treated patients except patients without a post baseline 
assessment of response will be excluded. 
 
Sample Size 
This study aims to assess the activity of ZW25 in advanced HER2 overexpressing 
endometrial cancers and carcinosarcomas as measured by the best overall response 
rate as determined by RECIST 1.1. Assuming we use a binary endpoint of response, 
defined as best overall response of CR or PR versus not (best overall response ≤24 
weeks from the start of treatment), a sample size of 25 patients provides 90% power to 
test the hypothesis that the response rate is promising (defined as 30% or higher) 
against a non-promising rate of 10% or lower. This calculation is based on historical data 
from studies with ineffective agents in a similar patient population, which have ORR < 
10% and PFS rate at 6 months < 20%,7,49-51 and uses a two-stage minimax Simon 
design, with Type I error=10%. Sixteen patients will be enrolled in the first stage and if 1 
response is observed among the 16 the study will end for lack of activity. If >=2 
responses out of 16 are observed, the study will continue to stage 2, where an additional 
9 patients will be enrolled for a total of 25. At the end of the study, if at least 5/25 
responses are observed then this will be considered a positive study (i.e. conclude that 
ORR is >10%). 
 
Based on historical accrual rates in similar populations, and with the increased prior lines 
of therapy that will not be allowed for eligibility, we anticipate successful enrollment of 2 
patients per month yielding a total accrual time of 18 months. Accrual will continue until 
25 evaluable for efficacy response patients are treated (i.e. 25 patients in efficacy 
population as defined above). 


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Sensitivity analysis for ORR will include in the calculation of ORR patients who do not 
have post baseline assessment of response as failures. 
 
All statistical analyses will be performed using the most recently released version of SAS 
statistical software, unless otherwise noted. For categorical variables, the number (n) 
and percent of each category within a parameter will be presented. For continuous 
variables, the sample size (n), mean, median, and standard deviation, as well as the 
minimum and maximum values, will be presented. Missing data will not be imputed 
unless otherwise stated. There will be a detailed description of patient disposition, 
patient demographics, and baseline characteristics. 
 
 
 
We will report the following statistics for the secondary objectives: 
 
The clinical benefit rate (CBR) of ZW25 therapy, defined as the percentage of patients 
with complete response (CR) + partial response (PR) + stable disease (SD) ≤24 weeks 
from the start of treatment will be reported and the 90% confidence interval will be 
estimated using exact binomial proportions 
 
Progression free survival (PFS), defined as the duration of time from start of treatment to 
time of recurrence, progression, or death due to any cause, whichever occurs first will be 
reported. Patients will be censored at last follow up date. The Kaplan Meier estimate of 
median PFS will be reported. 
 
Overall survival is defined as the duration of time from start of treatment to time of death 
due to any cause. Patients who are alive will be censored at last follow up date. The 
Kaplan Meier estimate of median OS will be reported. 
 
The duration of response (DOR) of ZW25 therapy, defined as the time from which 
measurement criteria are met for CR or PR (whichever status is recorded first) until the 
first date of documented disease progression, will be estimated using the Kaplan Meier 
method. Patients without documented progression will be censored at last follow up. 
 
Adverse events by the current version of Common Terminology Criteria for Adverse 
Events version 5 (CTCAE v5) will be tabulated in order to assess the safety profile and 
tolerability of ZW25therapy in patients with recurrent/persistent endometrial cancer. 
 
ADA titers are a continuous variable and these will be assessed descriptively for changes 
over time as part of exploratory aims. 
 
All patients will have their tumors molecularly profiled using the MSK-IMPACT platform, to 
evaluate for genomic alterations defined by MSK-IMPACT. Testing will (looking for 
presence/absence of genes at baseline and at end of study) be correlated to objective 
responses outcomes (binary covariates of CR or PR versus not) in an exploratory manner. 
Chi square of Fishers’ exact test will be used to test this association. A subset analysis of 
patients who respond and then progress and have post progression material for molecular 
profiling will be performed in order to determine the mechanism(s) underlying acquired 
resistance. Specifically, we will be looking for presence of genetic alterations (at progression 
compared to baseline) which based on their understood biological mechanism may explain 


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acquired resistance. This analysis will be descriptive with the intention of understanding 
genetic alterations over time (at progression) and the types of mutation alterations among 
patients who respond and then progress. Patients will be followed up for a minimum of 12 
months. Most variables above are binary (presence/absence) or expressed (yes/no) and 
they will be tested for association with response (yes/no) using Chi square of Fishers’ exact 
test. 
 
Serial pre- and post-treatment blood samples will be collected for cell-free tumor DNA 
analysis and sequenced using continuous quantitative methods (digital droplet PCR or 
hybridization capture next-generation sequencing) for the Rb, CD-K, PI3K- pathway 
alterations identified by pre-treatment and post-treatment tumor testing and descriptively 
correlated to clinical outcome. Binary covariates (presence/absence) will be tested for 
association with response (binary: CR or PR vs not) using Chi square of Fishers’ exact test. 
Circulating tumor DNA is a continuous variable and these will be assessed descriptively for 
changes over time as part of exploratory aims. 
 
 
15.0 
TOXICITIES/RISKS/SIDE EFFECTS 
The treating investigator or qualified designee will assess each subject to evaluate for 
potential new or worsening AEs as specified in the Schedule of Assessments (see 
Section 10.0) and more frequently if clinically indicated. Adverse experiences will be 
graded and recorded throughout the study and during the follow-up period according to 
NCI CTCAE Version 5.0. Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment. 
ZW25 Monitoring and Management of Adverse Events 
Infusion-related Reactions 
Some patients treated with IV infusions of therapeutic drugs have experienced 
concurrent infusion-related reactions (see CTCAE Version 5.0). The signs and 
symptoms may vary and include for example, headache, fever, facial flushing, pruritus, 
myalgia, nausea, chest tightness, dyspnea, vomiting, erythema, abdominal discomfort, 
diaphoresis, shivers, lightheadedness, hypotension, palpitations, and somnolence. 
Anaphylaxis might occur at any time during an infusion. 
 
While ZW25 is a fully humanized antibody, infusion reactions may occur. Infusion 
reactions consist of a symptom complex characterized by fever and chills, and may 
include nausea, vomiting, pain, headache, dizziness, dyspnea, hypotension, rash, and 
asthenia. Severe and potentially fatal reactions may include bronchospasm, 
anaphylaxis, angioedema, hypoxia, and severe hypotension. Infusion reactions may 
occur during or immediately following the initial infusion or at a later time point. While 
severe reactions usually occur during or immediate after infusion, onset and clinical 
course can be variable. 
 
Prior to dosing with ZW25, all patients must receive prophylactic treatment for infusion 
reactions consistent with institutional standards that includes a corticosteroid. The 


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recommended regimen also includes acetaminophen orally, diphenhydramine (or 
equivalent) orally or IV 30 minutes through 60 minutes prior to infusion of ZW25 
(recommended doses are: acetaminophen 650 mg, diphenhydramine 50 mg), and a 
corticosteroid (hydrocortisone, dexamethasone, or equivalent). If an alternative 
premedication regimen is thought to be required, approval from Zymeworks, Inc. should 
be sought. For patients who experience an infusion reaction despite initial 
premedication, additional prophylactic treatment may be added prior to subsequent 
doses, including an H2 blocker such as ranitidine as per institutional guidelines. 
 
In the event of an infusion reaction, ZW25 infusion should be interrupted and medical 
therapy administered according to institutional standard of care (which, depending upon 
severity of the event, may include but not be limited to use of H1 and H2 inhibitors, 
corticosteroids, oxygen, IV fluids, epinephrine, and bronchodilators). Patients should be 
evaluated and carefully monitored until complete resolution of signs and symptoms. 
ZW25 should be discontinued in patients who experience a life-threatening (Grade 4) 
infusion reaction. Patients who experience a Grade 3 infusion reaction may be retreated 
at the discretion of the investigator at the next scheduled treatment. Such patients 
should receive additional prophylactic medication that may include a corticosteroid, and 
the duration of the infusion should be increased. 
Infusions should be administered over 120 minutes through 150 minutes for the first 2 
doses. If tolerated, infusion time may be reduced to 90 minutes for the next 2 doses, with 
reduction to 60 minutes for subsequent infusions at the discretion of the treating 
physician. Patients who experience a Grade 1 or Grade 2 infusion reaction may resume 
infusion of drug at a reduced infusion rate (30% through 50% slower than initial rate). 
 
Samples will be collected from all treated patients for retrospective analysis to detect the 
presence of antibodies to ZW25 (i.e., ADA). In the event that an infusion reaction occurs 
or there is a suspicion of a hypersensitivity event, analysis of available samples collected 
to date for that patient may be performed. 
 
Potential Cardiotoxicity 
HER2 targeted therapies have been associated with cardiotoxicity. Therefore, only 
patients who have baseline normal left ventricular ejection fraction and no history of 
significant cardiac disease will be eligible for treatment with ZW25. Patients with a 
lifetime cumulative dose of anthracycline >300 mg/m2 or who have received 
anthracycline treatment within 90 days of the expected first dose of ZW25 are not 
eligible for treatment. 
Patients are monitored per the study-specific protocol for changes in cardiac function. 
Cardiac monitoring includes assessment of ECG (frequency and type of abnormalities 
using standard 12-lead ECG, including heart rate, PR interval, QRS complex, QTcF), 
and echocardiogram (estimation of ejection fraction). 


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Management of decreased left ventricular ejection fraction (LVEF), regardless of 
relationship to study drug, is described in Table 3 below. 
 
Table 3: 
Management Guidelines for LVEF Dysfunction 
 
Left Ventricular Dysfunction
Management
Symptomatic cardiac heart failure 
● Discontinue ZW25 
LVEF <40% 
● Do not administer ZW25 
● Repeat LVEF assessment within 4 weeks 
● If LVEF <40% is confirmed, discontinue ZW25 
LVEF below institutional limits of normal 
and ≥ 10% points below pre-treatment 
baseline 
● Do not administer ZW25 
● Repeat LVEF assessment within 4 weeks 
● If the LVEF has not recovered to within 10% 
points from baseline, discontinue ZW25 
LVEF 40% to ≤ 45% and decrease is < 
10% points from baseline 
● Continue treatment with ZW25 
● Repeat LVEF assessment within 4 weeks 
LVEF > 45% 
● Continue treatment with ZW25, as applicable 
 
Gastrointestinal Toxicity 
The most common ZW25-related gastrointestinal TEAEs (> 20%) were diarrhea and 
nausea. Two patients in Part 1/2 developed ZW25-related Grade 3 diarrhea (20 mg/kg), 
which subsequently resolved with medications. No patients in Part 3 developed ZW25 
Grade 3/4 gastrointestinal toxicity. 
Table 4: 
Management Guidelines for Potential Infusion-related Reactions 
Infusion Reaction CTCAE
v5.0Severity Grade 
Management
Grade 1: Mild, transient 
reaction 
Maintain infusion rate unless progression of symptoms to ≥ 
Grade 2; if symptoms worsen, refer to guidelines below 
Promethazine (or equivalent) 150 mg PO per day for nausea (or 
equivalent) 
Diphenhydramine (or equivalent) 25-50 mg PO or IV prn 
Methylprednisolone 125 mg (or equivalent) IV prn 


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Infusion Reaction CTCAE
v5.0Severity Grade 
Management
Grade 2: Moderate 
Interrupt infusion and disconnect infusion tubing from patient 
Promethazine (or equivalent) 150 mg PO per day for nausea 
Diphenhydramine (or equivalent) 25-50 mg PO or IV prn 
Methylprednisolone 125 mg (or equivalent) IV PRN) 
After recovery from symptoms, resume the infusion at 50% of the 
previous rate and if no further symptoms appear, gradually 
increase rate until infusion is completed. 
For subsequent dosing in future cycles, patients should be pre- 
medicated with dexamethasone (or equivalent) 8 mg PO BID the 
day prior to drug administration and acetaminophen (or 
equivalent) 650 mg PO and diphenhydramine (or equivalent) 25- 
50 mg PO 30-60 minutes prior to dosing. 
Grade 3: Severe, prolonged 
reaction 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 infusion and disconnect infusion tubing from 
subject 
Administer diphenhydramine (25-50 mg) IV (or equivalent) 
Administer IV steroids (methylprednisolone (or equivalent) up to 
0.5mg/kg Q 6h) to treat ongoing reaction and prevent recurrence 
Administer bronchodilators (nebulized albuterol/salbutamol, 2.5-5 
mg in 3 mL of saline or equivalent) as medically indicated 
Administer normal saline as medically indicated 
Administer epinephrine (0.2-0.5 mL of a 1:1000 dilution (0.2-0.5 
mg) SQ or IM) as medically indicated. Epinephrine should only 
be used if all other treatment methods fail to manage the 
infusion-related reaction. 
Advise patient to seek emergency treatment and notify 
investigator/clinic if the infusion-related symptoms recur after 
discharge from clinic. 
Report as a serious adverse event 
Grade 4: Life-threatening 
consequences, urgent 
intervention indicated 
Management as for Grade 3 reaction and permanently 
discontinue study medication treatment 
 
Monitoring and Management of Diarrhea Following the Administration of Study 
Treatment: ZW25-associated Diarrhea 
Mild to moderate diarrhea has been frequently reported in patients treated with ZW25. 
Patients will be prescribed loperamide as a prophylactic measure prior to Cycle 1 Day 
1 of treatment and will be instructed on its use. Patient should be advised to contact 
their treating physician at the first sign of diarrhea and should be treated according to 
standard institutional practice. One suggested regimen would be the administration of 
2-4mg of loperamide at the first sign of loose stool, with repeat dosing every 2 hours 
until symptoms resolve and up to a maximum of 16mg/day.46 For Diarrhea that is G3 
despite use of optimal anti-diarrheal treatment, hold drug until resolved to ≤ grade 1, 
then resume at a lower dose level. 


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Monitoring and Management of Nausea and Vomiting Following the 
Administration of ZW25 
Nausea and vomiting have been reported in patients treated with ZW25. Patients 
should be advised to contact their treating physician at the first sign of vomiting or 
worsening nausea. Patients should be treated according to the American Society of 
Clinical Oncology (ASCO) Clinical Practice Guidelines for the use of antiemetics47 
outlined in Table 5. 
Table 5: 
Management of Nausea and Vomiting 
Severity Grade
(CTCAE v5.0 Grade) 
Management
Grade 1
Administer single 8 mg dose of dexamethasone before therapy
Grade 2 
Administer a 5- HT3 receptor antagonist on day 1 (e.g. 
palonosetron, granisetron, or ondansetron) in combination with 
dexamethasone on days 1-3 or treat as per institutional 
guidelines. Aprepitant may be added to the combination. 
Grades 3 and 4 
Administer a neurokinin 1 receptor antagonist (e.g. aprepitant 
on days 1-3 or fosaprepitant on day 1), in combination with a 5- 
HT3 receptor antagonist on day 1 only, and dexamethasone on 
days 1-3 or 1-4 or treat as per institutional guidelines. 
For G3 nausea/vomiting despite optimal use of antiemetics, 
hold drug until resolved to ≤ grade 1, then resume at a lower 
dose level. 
 
Other non-hematological toxicities: Except adverse events related to underlying disease, 
Grade 3 fatigue, isolated symptomatic G3 biochemistry abnormalities that last for < 7 
days including electrolyte abnormalities that respond to medical intervention, for a Grade 
3 event, hold study drug until resolved to ≤ Grade 1, then resume at lower level. For any 
grade ≥ 3 cardiac events and for Grade 4, non-hematological toxicities, permanently 
discontinue ZW25 treatment. 
 
For any Grade 3 hepatic toxicity that does not resolve to baseline within 7 days, an 
abdominal CT scan must be performed to assess whether it is related to disease 
progression. 
 
Re-treatment Criteria 
To Begin a New Cycle of Treatment or continue treatment within a cycle 
For a patient to begin a new cycle or continue a cycle of therapy, the following criteria must 
be met. 
 
 
ANC must be ≥ 1.0x109/L (1,000/L) 
 
Platelet count must be ≥ 75 x 109/L (75,000/L) 


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 
All non-hematologic toxicities for which a causal association to study treatment cannot 
be ruled out, must be ≤ Grade 1 (except alopecia) or returned to baseline. 
 
 
If the patient does not meet these criteria, dosing will be delayed and the patient should 
be re-evaluated within 48-72 hours. Dosing with may resume if these criteria have been met. 
 
If treatment is delayed due to treatment-related toxicity longer than one cycle, then the 
patient should be removed from study treatment. In such cases, continuation of study 
treatment may be considered for those patients who have experienced clinical benefit if 
agreed upon by the principal investigator and Zymeworks. 
 
The use of granulocyte growth factors in accordance with ASCO guidelines may be 
implemented at the discretion of the treating physician. 
Follow-up for AEs Leading to Discontinuation 
Patients who discontinue study treatment for an AE or an abnormal laboratory value 
must be followed at least once a week for 4 weeks, and subsequently at 4-week 
intervals until resolution or stabilization of the adverse event or laboratory abnormality, 
whichever occurs first. 
Dose Modification Guidelines 
ZW25 Dose Reduction Following an AE 
ZW25 dose may be reduced at the discretion of the Investigator after discussion with 
Zymeworks. Patients who develop adverse events requiring an interruption of ZW25 
may resume treatment at a reduced dose level as shown in Table 6. 
Table 6:    ZW25 Dose Modification Guidelines 
Regimen
If the patient was receiving ZW25 at:
Dose 
Level 1 
20mg/kg intravenously (IV) every two weeks 
Dose 
Level -1 
15 mg/kg every two weeks 
Dose 
Level -2 
10 mg/kg every two weeks 
*Reduction of the ZW25 dose below 10 mg/kg will not be permitted. 
 
Overdose and Medication Error 
 
Overdose: There is no known treatment/antidote available for ZW25. Supportive 
measures should be instituted if an instance arises in which a patient suffers an 
overdose of any study drug. 


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Medication Error: Zymeworks must be immediately notified in the event of error in 
prescribing, dispensing, administering and/or use of ZW25 or of any study drug, and the 
event must be reported on the eCRF. 
 
If an error resulted in a serious adverse event, a Serious Adverse Event Report Form 
must be submitted within 24 hours of the event. 
15.1 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
Death 
 
A life-threatening adverse event 
 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
A congenital anomaly/birth defect 
 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered 
an SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational 
treatment/intervention and is related to a screening test or procedure (i.e., a screening 
biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office 
per IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be 
submitted within 5 calendar days of the event. All other SAEs must be submitted within 
30 calendar days of the event. 
The report should contain the following information: 
 
The date the adverse event occurred 


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 
The adverse event 
 
The grade of the event 
 
Relationship of the adverse event to the treatment(s) 
 
If the AE was expected 
 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
 
If an amendment will need to be made to the protocol and/or consent form 
 
If the SAE is an Unanticipated Problem 
15.2. External SAE Reporting 
For IND/IDE protocols: 
The SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FDA by the IND Office 
 
15.2.1 Pharmaceutical Specific Reporting 
Recording Adverse Events and Serious Adverse Events 
AEs (including SAEs) will be documented on the AE eCRF and monitored continuously 
throughout the study from the time of informed consent until 30 days after the patient’s 
last study treatment or until the event has resolved or stabilized or becomes chronic, 
whichever comes first. AEs attributed to study procedures should also be documented 
on the AE eCRF. 
15.2.2 Adverse Events of Special Interest (AESI) 
An adverse event of special interest (AESI) (serious or non-serious) is one of scientific 
and medical concern specific to the Grantor’s product for which ongoing monitoring and 
rapid communication by the investigator to the Grantor could be appropriate. These 
include 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. These are reportable 
to the Grantor via monthly listings, unless they are serious and assessed by the 
investigator as Related to zanidatamab, in which case they are reportable to Zymeworks 
Drug Safety in an expedited manner using a CIOMS-I form. 
 
The Investigator will promptly supply all information identified and requested by the 
Grantor regarding the SAE, AESI, or pregnancy. 
Reporting to Zymeworks 
Any SAE assessed by the Investigator as Related to a zanidatamab or pregnancy that 
occurs in a study subject between the time of first study drug administration and 30 days 
after last study drug administration will be reported to Zymeworks Drug Safety 


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(drugsafety@zymeworks.com) within 24 hours of first awareness of the event. For SAE 
reporting, including those that are expedited, completed CIOMS-I forms will be provided 
to Zymeworks. Any SAEs assessed by the Investigator as NOT Related to zanidatamab 
should be reported to Zymeworks via monthly listings. 
 
Any SAEs deemed related to zanidatamab occurring beyond 30 days after the last study 
drug administration should be reported to Zymeworks (drugsafety@zymeworks.com). 
SADRs 
A full report for SAEs that are related to the Product shall be transmitted to Zymeworks 
on a CIOMS-I form within 24 hours of the awareness date. 
Other SAEs 
SAEs that are unrelated to the Product shall be transmitted to Zymeworks within thirty 
(30) calendar days of the awareness date via monthly listings. 
AESIs 
Non-serious AESIs shall be forwarded to Zymeworks within thirty (30) calendar days of 
the awareness date via monthly listings. 
Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as 
defined herein, any reports of pregnancy where the fetus may have been exposed to the 
Product, shall be transmitted to Zymeworks within 24 hours of the awareness date. 
Pregnancies will be followed up until the outcome of the pregnancy is known, whenever 
possible, based upon due diligence taken to obtain the follow-up information. 
 
Reporting a Pregnancy 
Pregnancy and lactation are exclusion criteria. Zymeworks must be immediately notified 
in the event of a pregnancy occurring during the course of the study and through 7 
months after a patient’s last dose of ZW25 whichever is earlier. Pregnancy is not to be 
reported as an AE; the CIOMS-I form should be used to report a pregnancy. All reported 
pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be 
reported as serious adverse events (Important Medical Events). The reporting 
procedures will be followed, including pregnancies and pregnancy outcomes listed 
above are reportable to Zymeworks in the same timeframe as SAEs which are assessed 
by the investigator as Related to zanidatamab. If the pregnancy continues to term, the 
outcome (health of infant) must also be reported. 
 
16.0 
PROTECTION OF HUMAN PARTICIPANTS 
The responsible principal investigator (PI) will ensure that this study is conducted in 
agreement with the declaration of Helsinki. The study will seek to protect the rights of 


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human subjects in every way. The potential risks, including adverse drug reactions and 
potential benefits in terms of pain control will be discussed in detail with the patients. 
Potential side effects as outlined above will be discussed with the patients. No patient 
will be required to participate in the study and participation, or refusal to do so, will not 
affect the patient’s care or treatment. 
Participation will be purely voluntary, patient confidentiality will be maintained. No results 
of the study will be presented or discussed in a fashion that will allow identification of a 
patient in the study. All adverse events will be fully reported to the IRB in a timely fashion 
as required. 
16.1 
Privacy 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and 
disclosure of protected health information will be limited to the individuals/entities 
described in the Research Authorization form. A Research Authorization form must be 
approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized de identified information collected for the 
purposes of this study may be shared with other qualified researchers. Only researchers 
who have received approval from MSK will be allowed to access this information which 
will not include protected health information, such as the participant’s name, except for 
dates. It is also stated in the Research Authorization that their research data may be 
shared with others at the time of study publication. 
 
16.2 
Data Management 
A Clinical Research Coordinator (CRC) will be assigned to the study. The responsibilities 
of the CRC include project compliance, data collection, extraction and data entry, data 
reporting, coordination of the activities of the protocol study team and, of the flow of 
regulatory compliance. 
The data collected for the study will be entered into a secure database (Medidata 
RAVE). All routine blood test results required per protocol will be captured in Medidata 
RAVE in addition to the baseline medical conditions and disease information, response 
assessments, off-study documentation, and toxicity grade and attribution. Source 
documentation will be available to support the electronic patient record. 
MSKCC will hold the IND and will be responsible for all safety monitoring. All SAEs will 
be reported to the MSKCC IRB (as applicable). The safety of the study will be monitored 
by the MSKCC Data and Safety Monitoring Committee. 


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Weekly registration reports will be generated by the CRC and reviewed by the PI to 
monitor patient accruals and completeness of registration data. Routine data quality 
reports will be generated to assess missing data and inconsistencies. 
Accrual rates and extent and accuracy of evaluations and follow-up will be monitored 
periodically throughout the study. Recurrent lapses in data collection, prospective and 
retrospective deviations will be discussed with the study team and a corrective action 
plan will be generated and shared with the team. Accrual goals and factors impacting 
accrual goals will be discussed at the weekly GMO Protocol meetings. 
If accrual proceeds more quickly than anticipated, it may be slowed or staggered at the 
discretion of the Principal Investigator, to account for safety concerns or data 
management resources. 
Final data sets for publication are required to be locked and stored centrally for potential 
future access requests from outside entities. 
16.3 
Quality Assurance 
Data and project enrollment will be monitored on an ongoing basis by the Principal 
Investigator. The CRC will inform the PI about the number of patients enrolled, the 
number of patients in follow-up, and any other outstanding issues protocol related. A log 
will be maintained of all patients consented and treated. The study data will be assessed 
for completeness by the PI. Random-sample data quality and protocol compliance audits 
will be conducted by the study team at minimum of two times per year or more frequently 
if problems are encountered. 
Biweekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to 
assess missing data and inconsistencies. Enrollment logs will be sent to Zymeworks to 
facilitate drug inventory. These enrollment logs do not contain PHI. 
16.4 
Data and Safety Monitoring 
The Data and Safety Monitoring Plan utilized for this study must align with the MSK DSM 
Plan, where applicable. 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering were 
approved by the National Cancer Institute in August 2018. The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials.” 
There are several different mechanisms by which clinical studies are monitored for data, 
safety and quality. At a departmental/PI level there exists procedures for quality control 


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by the research team(s). Institutional processes in place for quality assurance include 
protocol monitoring, compliance and data verification audits, staff education on clinical 
research QA and two institutional committees that are responsible for monitoring the 
activities of our clinical trials programs. The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Deputy Physician-In-Chief, 
Clinical Research. 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required. 
The MSK DSMB monitors phase III trials and the DSMC monitors non-phase III trials. 
The DSMB/C have oversight over the following trials: 
 
MSK Investigator Initiated Trials (IITs; MSK as sponsor) 
 
External studies where MSK is the data coordinating center 
 
Low risk studies identified as requiring DSMB/C review 
The DSMC will initiate review following the enrollment of the first participant/or by the 
end of the year one if no accruals and will continue for the study lifecycle until there are 
no participants under active therapy and the protocol has closed to accrual. The DSMB 
will initiate review once the protocol is open to accrual. 
 
 
17.0 
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18.0 
APPENDICES 
Appendix A: Eastern Cooperative Oncology Group (ECOG) Performance Status Scale52 
 
GRADE 
SCALE 
0 
Fully active, able to carry out all pre-disease performance without restriction. 
(Karnofsky 90-100) 
1 
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. 
(Karnofsky 70-80) 


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2 
Ambulatory and capable of all self-care but unable to carry out work 
activities. Up and about more than 50% of waking hours. (Karnofsky 50-60) 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. (Karnofsky 30-40) 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair. (Karnofsky 10-20) 


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Appendix B: Anaphylaxis Precautions 
 
 
EQUIPMENT NEEDED 
• Tourniquet 
• Oxygen 
• Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance with standard 
practice 
• Antihistamines 
• Corticosteroids 
• Intravenous infusion solutions, tubing, catheters, and tape 
 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, the following 
procedures should be performed: 
1. Stop the study treatment infusion. 
2. Apply a tourniquet proximal to the injection site to slow systemic absorption of study treatment. Do 
not obstruct arterial flow in the limb. 
3. Maintain an adequate airway. 
4. Administer antihistamines, epinephrine, or other medications as required by patient status and 
directed by the physician in charge. 
5. Continue to observe the patient and document observation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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