A Study of MRG002 in the Treatment of HER2-positive/HER2-low Locally Advanced or Metastatic Gastric/Gastroesophageal Junction Cancer.

An Open-label, Multi-center, Phase II Clinical Study to Evaluate the Safety, Efficacy and Pharmacokinetics of MRG002 in Patients With HER2-positive/HER2-low Locally Advanced or Metastatic Gastric/ Gastroesophageal Junction Cancer.

The objective of this study is to assess the safety, efficacy, pharmacokinetics, and immunogenicity of MRG002 as single agent in patients with HER2-positive /HER2-low locally advanced or metastatic gastric/ gastroesophageal junction cancer.

There are two cohorts in this study. HER2-positive and HER2-low patients will be allocated to cohort 1 and cohort 2, respectively. When the 20th, 40th, or 60th patient in each cohort completed at least one post-baseline tumor assessment, the Safety Monitoring Committee will review the safety and efficacy of these patients to determine dose selection, enrollment continuation, study population, and sample size.

Inclusion Criteria:

1. Willing to sign the ICF and follow the requirements specified in the protocol.
2. Aged ≥18.
3. Life expectancy ≥ 3 months.
4. Patients with histologically or cytologically confirmed gastric/ gastroesophageal junction cancer.
5. In Cohort 1, a positive HER2 test result defined as follows: IHC 3+ or IHC 2+ and ISH positive. In Cohort 2, low HER2 expression defined as follows: IHC 1+, or IHC 2+ and ISH negative.
6. Documented tumor progression or intolerance during or after at least one prior line of platinum- and/or fluoropyrimidine-based chemotherapy ± anti-HER2 (trastuzumab or equivalent) therapy.
7. Willing and able to provide adequate archival tumor tissue samples for HER2 status confirmation by central laboratory.
8. Cohort 1 patients, who have received prior anti-HER2 therapy, are willing to undergo fresh tissue biopsy to confirm HER2 status as assessed by the investigator to be feasible and safe.
9. Patients must have at least one measurable tumor lesion according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
10. The score of ECOG for performance status is 0 or 1 with no deterioration within 2 weeks prior to the first dose of the study drug.
11. Organ function must meet the basic requirements.

Exclusion Criteria:

1. Patients with the following pathological diagnosis: squamous cell carcinoma, carcinoid tumor, neuroendocrine carcinoma, undifferentiated carcinoma, or other unclassifiable gastric cancer.
2. Peripheral neuropathy ≥ Grade 2 per CTCAE 5.0.
3. Prior treatment with HER2-targeted ADC.
4. Known allergic reaction to any component or excipient of MRG002, or known allergic reaction to trastuzumab or other prior anti-HER2 or other monoclonal antibodies ≥ Grade 3.
5. Presence of untreated or uncontrolled central nervous system (CNS) metastases.
6. Patients received chemotherapy, biological therapy, radical radiotherapy or other anti-tumor treatment within 3 weeks prior to the first dose of the study drug.
7. Any severe cardiac dysfunction, history of myocardial infarction, stroke, or transient ischemic attack (TIA) within 6 months prior to enrollment.
8. Pulmonary embolism or deep venous thrombosis within 3 months prior to the first dose of the study drug.
9. Tumor lesions with bleeding tendency or treated with blood transfusion within 2 weeks prior to the first dose of the study drug.
10. Toxicities due to prior anti-cancer therapy have not resolved to ≤ Grade 1 (CTCAE v5.0).
11. Concurrent malignancy within 5 years prior to enrollment.
12. Uncontrolled high blood pressure and diabetes.
13. History of ventricular tachycardia or torsades de pointes. Any clinically significant abnormalities in rhythm, conduction, or morphology on the resting ECG.
14. History of moderate to severe dyspnea at rest due to advanced cancer or its complications, severe primary lung disease, current need for continuous oxygen therapy, or clinically active interstitial lung disease (ILD) or pneumonitis.
15. Patients who had undergone thoracotomy, laparotomy, or surgery requiring general anesthesia without complete recovery within 4 weeks prior to the first dose of the study drug.
16. Active hepatitis B, active hepatitis C, syphilis or human immunodeficiency virus (HIV) infection.
17. Active uncontrolled bacterial, viral, fungal, rickettsial, or parasitic infection requiring intravenous anti-infective therapy within 2 weeks prior to the first dose of study drug.
18. Any severe and/or uncontrolled systemic diseases.
19. Use of systemic corticosteroids within 4 weeks prior to the first dose of study drug.
20. Use of potent CYP3A4 inhibitors or potent CYP3A4 inducers within 2 weeks prior to the first dose of study drug or need to continue during the study.
21. Female patents with a positive serum pregnancy test or who are breast-feeding or who do not agree to take adequate contraceptive measures during the treatment and for 180 days after the last dose of study treatment.
22. Other conditions inappropriate for participation in this clinical trial, at the discretion of the investigator.