Trial of ZW25 in Patients With Advanced HER2-expressing Cancers

Part 1, Dose Escalation: Patients with any HER2-expressing cancer that is either HER2 1+, 2+
or 3+ by immunohistochemistry (IHC) and has progressed after all standard of care therapies
will receive escalating doses of ZW25 in order to identify either the highest dose of study
drug possible that will not cause unacceptable side effects or the dose of study drug which
is thought to be associated with optimal biologic activity.

Part 2, Dose Expansion: Patients will be enrolled into one of the below cohorts based the
level of HER2 expression and cancer type.

- Cohort 1: HER2 IHC 2+/FISH negative breast cancer

- Cohort 2: HER2 IHC 3+ or HER2 IHC 2+/FISH positive breast cancer

- Cohort 3: HER2 IHC 2+/FISH negative gastric/ GEJ cancer

- Cohort 4: HER2 IHC 3+ or HER2 IHC 2+/FISH positive gastric/GEJ cancer

- Cohort 5: Any other HER2 IHC 3+ or FISH positive cancer

Patients in Part 2 will receive the dose of study drug identified in Part 1 of the study.
These patients will be followed to further evaluate the safety of ZW25 as well as to explore
anti-tumor activity.

Part 3, Combination Therapy Expansion: Patients with HER2-expressing breast or gastric/GEJ
cancers will be treated with ZW25 in combination with one of several chemotherapy regimens
including paclitaxel, capecitabine and vinorelbine.

Inclusion Criteria:

1. HER2-expressing cancer as follows:

Part 1:

Any locally advanced (unresectable) and/or metastatic HER2-expressing (HER2 1+, 2+, or
3+ by IHC) cancer that has progressed after receipt of all therapies known to confer
clinical benefit

- HER2-overexpressing (3+ by IHC) or HER2 2+ and FISH positive breast cancer must
have progressed after prior treatment with trastuzumab, pertuzumab, and T‑DM1

- HER2-overexpressing (3+ by IHC) or HER2 2+ and FISH positive gastric cancer must
have progressed after prior treatment with trastuzumab

Part 2:

− Locally advanced (unresectable) and/or metastatic cancer that has progressed after
receipt of all therapies know to confer clinical benefit (unless ineligible to receive
a specific therapy) as follows:

- Cohort 1: HER2 IHC 2+/FISH negative breast cancer

- Cohort 2: HER2 IHC 3+ or HER2 IHC 2+/FISH positive breast cancer

- Cohort 3: HER2 IHC 2+/FISH negative gastric/GEJ cancer

- Cohort 4: HER2 IHC 3+ or HER2 IHC 2+/FISH positive gastric/GEJ cancer

- Cohort 5: Any other HER2 IHC 3+ or FISH positive cancer

- Pts with colorectal cancer must be KRAS wild-type

- Pts with NSCLC must have ALK wild-type, EGFR wild-type, and ROS1 fusion
negative

Part 3:

Locally advanced (unresectable) and/or metastatic cancer as follows:

- HER2 IHC 1+ or IHC2+/FISH- breast cancer patients who have received at least 1
and no more than 3 prior systemic chemotherapy regimens

- HER2 IHC 3+ or IHC 2+/FISH+ breast cancer patients who have received prior
therapy with trastuzumab, pertuzumab, and T-DM1, at least 1 and no more than 3
prior systemic chemotherapy regimens

- HER2 IHC 2+ or 3+ FISH+ or FISH- gastric/GEJ cancer patients who have received at
least 1 and no more than 3 prior systemic chemotherapy regimens.

2. ≥ 18 years of age

3. ECOG 0 or 1

4. Adequate hepatic function, as follows:

- AST ≤2.5 x ULN (if liver or bone mets are present, ≤5 x ULN)

- ALT ≤2.5 x ULN (if liver or bone metastases are present, ≤5 x ULN)

- Total bilirubin ≤1.5 x ULN

5. Adequate renal function (within normal limits or calculated glomerular filtration rate
>50)

6. Hematological function:

- ANC ≥1.5 x 10⁹/L

- Platelet count ≥75 x 10⁹/L (Parts 1 and 2), ≥100 x 10⁹/L (Part 3)

- Hemoglobin ≥9 g/dL

- PT and PTT <1.5 x ULN

7. Adequate cardiac left ventricular function

8. For Part 1, cohorts 1-3: evaluable disease (per RECIST version 1.1). For Part 1,
cohorts 4-6 and Parts 2 and 3: measurable disease (per RECIST version 1.1)

9. Able to provide a fresh formalin-fixed, paraffin-embedded (FFPE) tumor sample for
central evaluation of HER2 status prior to enrolment; if a fresh biopsy is not
feasible, sponsor approval is required and archived tumor biopsy must be provided for
centralized testing by sponsor

- For Parts 1 and 3, eligibility may be based on local read of fresh or archived tumor
biopsy. Archived or fresh FFPE biopsy must be provided for retrospective centralized
review.

10. Willingness to use 2 methods of birth control during the study and for 12 months after
the last dose of ZW25

Exclusion Criteria:

1. Experimental therapies within 4 weeks before first ZW25 dosing

2. Other cancer therapy including chemotherapy, small molecules, and antibodies within 5
half-lives of the cancer therapy before first ZW25 dosing

3. Anthracyclines within 90 days before first ZW25 dosing or lifetime load exceeding 300
mg/m² adriamycin or equivalent

4. Trastuzumab, pertuzumab, lapatinib, or T‑DM1 within 3 weeks before first ZW25 dosing

5. Untreated brain metastases (pts with treated brain mets who are off steroids and
anticonvulsants and stable for at least 1 month at the time of Screening are eligible)

6. Pregnant or breast-feeding women

7. History of life-threatening hypersensitivity to monoclonal antibodies or to
recombinant proteins or excipients in drug formulation

8. Acute or chronic uncontrolled renal disease, pancreatitis or liver disease (with
exception of patients with Gilbert's Syndrome, asymptomatic gall stones, liver
metastases, or stable chronic liver disease per investigator assessment)

9. Peripheral neuropathy >Grade 2

10. Clinically significant interstitial lung disease

11. Known active hepatitis B or C or known infection with HIV

12. Immunosuppressive corticosteroids equivalent to >15mg/day of prednisone within 2 weeks
before first ZW25 dose

13. QTc Fridericia (QTcF) >450 ms

14. Having clinically significant cardiac disease such as ventricular arrhythmia requiring
therapy, uncontrolled hypertension or any history of symptomatic CHF

15. Having known myocardial infarction or unstable angina within 6 months before first
ZW25 dosing