An open-label, multicenter, phase I dose-escalation study to assess the safety, Pharmacokinetic (PK), immunogenicity and preliminary anti-tumor activity of ZV0203 in patients with HER2-Positive advanced solid tumors

Inclusion Criteria:

1. Being willing and capable of signing a written informed consent form (ICF).

2. Aged ≥18 or older at the time of signing the ICF.

3. Pathologically diagnosed as having an unresectable locally advanced or metastatic solid tumors, refractory or intolerant to standard therapy, or with no standard therapy available.

4. Having HER2-positive disease, i.e. HER2 positive by in situ hybridization on previously collected tumor tissue and/or immunohistochemistry of 3+.

5. The Eastern Cooperative Oncology Group Performance Status (ECOG) performance status score is 0 or 1.

6. Echocardiography (ECHO) or multi-gated acquisition (MUGA) scan shows a left ventricular ejection fraction of ≥ 50%.

7. Good hematology and end-organ function, with laboratory results within 14 days prior to the first study treatment (Cycle 1, Day 1) meeting the following criteria:

   • Absolute neutrophil count ≥ 1,500/mm3
   • Platelet count ≥ 100,000/mm3 and no transfusion within 14 days after obtaining a hematology laboratory sample at screening
   • Hemoglobin ≥ 9.0 g/dL
   • Total bilirubin ≤ 1.5 ×upper limit of normal (ULN); subjects with confirmed/suspected Gilbert's disease, bilirubin ≤ 3 × ULN
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN; ≤ 5 × ULN if there is liver metastasis
   • Serum creatinine ≤ 1.5 × ULN or estimated glomerular filtration rate > 40 mL/min/1.73 m2
   • Prothrombin time and activated partial thromboplastin time ≤ 1.5 × ULN. It is applicable only to subjects who have received no therapeutic anticoagulant therapy and subjects who have received therapeutic anticoagulant therapy at a stable dose.

8. The investigator determined that the life expectancy of the subjects is ≥12 weeks.

9. For women of childbearing potential, their pregnancy test must be negative for enrollment, and they must agree to take highly effective contraceptive measures when enrolled, during treatment and 90 days after the last dose of the investigational drug (see section 6.1.3). Women are considered to be of childbearing potential from menarche to menopause (after at least 12 months without menstruation) unless they are permanently infertile (due to hysterectomy, bilateral salpingectomy or bilateral oophorectomy).

10. For men, they must be surgically sterile or agree to take highly effective contraceptive measures when enrolled, during treatment and 90 days after the last dose of the investigational drug (see section 6.1.3 ).

Exclusion Criteria:

1. Subjects with symptomatic brain metastases or soft meningeal disease known to require steroid therapy. Subjects diagnosed with brain metastases in the past can participate in the study if they have completed the treatment, recovered from the acute reaction of radiotherapy or surgery prior to enrollment, have discontinued the use of corticosteroids for the treatment of these metastases, and have been clinically stable and neurologically stable without anticonvulsants for at least 4 weeks prior to enrollment.

2. Subjects who are suffering from uncontrolled or major cardiovascular disease, including any of the following circumstances:

   • Baseline QT Interval Corrected Using Fridericia's Formula >450 msec or congenital long QT syndrome.
   • Subjects who have a history of symptomatic congestive heart failure or current symptomatic congestive heart failure (NYHA Grade III-IV) or severe arrhythmias requiring treatment.
   • Subjects who have a history of myocardial infarction or unstable angina within 6 months prior to first dose of ZV0203.
   • Subjects who have a clinically significant resting bradycardia (< 50 beats/min).
   • Subjects who have a history of grade II (Mobitz II) or grade III cardiac conduction block (subjects with pacemakers may participate in this study if they have no history of syncope or clinically relevant arrhythmias during pacemaker use).
   • Subjects who have a history of complete left bundle branch block.

3. Subjects who have a history of clinically significant lung disease (e.g., interstitial pneumonia, pulmonary fibrosis, and severe radiation pneumonia) or suspicion of these diseases by imaging at screening.

4. Subjects who have a history of ocular abnormalities and judged to be ineligible for enrollment by the investigator.

5. Subjects who have received any anticancer treatment or investigational therapy within 4 weeks prior to the first dose of ZV0203.

6. Subjects who have received hormone therapy within 14 days prior to the first dose of ZV0203, except hormone therapy for non-cancer related conditions (e.g. alternative therapies of insulin and hormone for diabetes).

7. Subjects who have undergone major surgery or scheduled surgery for any reason within 4 weeks prior to screening or those the investigator believe may require surgery.

8. Toxicity of prior anticancer therapy does not improve to NCI-CTCAE V5.0 Grade 0 or 1, except for alopecia and laboratory values listed according to the inclusion criteria.

9. Subjects who have a history of other malignancies, except adequately treated non-melanoma skin cancer, radically treated in situ disease or other solid tumors that have been radically treated and free of evidence of disease for at least 2 years.

10. Subjects who are suffering an active infection that is difficult to control with systemic therapy.

11. Subjects who are suffering known active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C).

12. Subjects who are known to have a history of human immunodeficiency virus infection.

13. Subjects who are suffering a concomitant disease that may increase the risk of toxicity in the judgment of the investigator.

14. Subjects who are known to be allergic to any component of ZV0203.

15. Subjects who have a history of intolerance to pertuzumab or Trastuzumab emtansine (e.g. grade 3 or grade 4 infusion-related reactions).