Exploratory Study on the Efficacy and Safety of Trastuzumab Rezetecan in the Treatment of HER2-Expressiong Advanced Solid Tumor

Exploratory Study on the Efficacy and Safety of Trastuzumab Rezetecan in the Treatment of HER2-Expressiong Advanced Solid Tumor

The goal of this clinical trial is to learn if Trastuzumab Rezetecan can treat advanced solid tumors with HER-2 expression in adult participants.

The main question it aims to answer is: What is the objective response rate of Trastuzumab Rezetecan in adult patients with HER-2 expressed advanced solid tumors? Participants will receive intravenous infusion of Trastuzumab Rezetecan on Day 1 of each 21-day treatment cycle. The dosage is 4.8 mg/kg per cycle; participants with a body weight of 85 kg or above will receive a fixed dose of 408 mg every 3 weeks.

Inclusion Criteria:

1. Male and female participants aged 18 years or older.

2. Participants with locally advanced, unresectable or metastatic solid tumors who have progressed after at least one prior systemic therapy for advanced/metastatic disease, or have no satisfactory alternative treatment options. Eligible tumor types include but are not limited to biliary tract cancer, endometrial cancer, urothelial carcinoma, pancreatic cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, head and neck adenocarcinoma (salivary gland adenocarcinoma, lacrimal gland adenocarcinoma, adenocarcinoma of unknown primary in the neck), cervical cancer, ovarian cancer and adenocarcinoma of unknown primary. Breast cancer is excluded.

3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.

4. Confirmed HER2 expression defined as IHC 1+, 2+ or 3+ (per GC criteria).

5. Willing and able to provide adequate tumor specimens for central pathological re-testing of HER2 status. For participants previously treated with anti-HER2 therapy, tumor specimens obtained after the last anti-HER2 treatment are optional.

6. At least one measurable lesion at baseline per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

7. Adequate organ and bone marrow function within 14 days prior to enrollment, meeting the following criteria:

   Hemoglobin ≥ 9 g/dL; Platelet count ≥ 100,000/mm³; Absolute neutrophil count (ANC) ≥ 1500/mm³; Serum albumin ≥ 3.0 g/dL; Prothrombin time (PT), activated partial thromboplastin time (aPTT) and International Normalized Ratio (INR) ≤ 1.5 × upper limit of normal (ULN); Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 × ULN; ≤ 5 × ULN for participants with liver metastases; Total bilirubin ≤ 1.5 × ULN for participants without liver metastases; ≤ 3 × ULN for participants with Gilbert's syndrome or liver metastases at baseline; Creatinine clearance ≥ 30 mL/min (calculated by the Cockcroft-Gault formula)

8. Left ventricular ejection fraction (LVEF) ≥ 50% assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days prior to enrollment.

Exclusion Criteria:

Participants meeting any of the following conditions are ineligible for this study:

1. Presence of any severe and/or uncontrolled diseases:

   • Poorly controlled blood pressure (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg); poorly controlled diabetes (fasting blood glucose [FBG] > 10 mmol/L).
   • Grade ≥ 2 myocardial ischemia, myocardial infarction, arrhythmia (QTc interval ≥ 470 ms), or Grade ≥ 2 congestive heart failure (per New York Heart Association [NYHA] classification).
   • Active or uncontrolled severe infections (Grade ≥ 2 per NCI CTCAE) requiring systemic antibacterial, antifungal or antiviral therapy, including pulmonary tuberculosis.
   • History of active tuberculosis.
   • Uncontrolled ascites, pericardial effusion or pleural effusion requiring repeated drainage.

2. Active hepatitis: Liver function not meeting the inclusion criteria. Hepatitis B: HBV DNA ≥ 2000 IU/mL or ≥ 10^4 copies/mL.Hepatitis C: HCV RNA ≥ 2000 IU/mL or ≥ 10^4 copies/mL. Participants with viral load below the above thresholds after nucleoside antiviral therapy are eligible. Chronic hepatitis B virus carriers with HBV DNA < 10^4 IU/mL must receive concurrent antiviral treatment throughout the study for enrollment.

3. History of immunodeficiency diseases, including HIV positivity or other acquired/congenital immunodeficiency disorders.

4. History of allogeneic solid organ transplantation or allogeneic hematopoietic stem cell transplantation.

5. Confirmed meningeal metastasis, spinal cord metastasis or spinal cord compression.

6. Within 6 months prior to the first study drug administration, presence of esophageal gastric varices, severe ulcers, unhealed wounds, gastrointestinal perforation, abdominal fistula, gastrointestinal obstruction, intra-abdominal abscess, acute gastrointestinal bleeding, extensive intestinal resection (partial colectomy or extensive small bowel resection complicated with chronic diarrhea), Crohn's disease, ulcerative colitis or long-standing chronic diarrhea.

7. Unhealed or poorly healing wounds, or active ulcers.

8. Toxicities from prior anti-tumor therapy have not resolved to Grade 0 or 1 per NCI CTCAE version 5.0.

9. Received major surgery, incisional biopsy or significant traumatic injury within 28 days before study treatment initiation; or with long-standing unhealed wounds or fractures.

10. History of severe hypersensitivity reactions to monoclonal antibodies; known allergy to the active ingredients or excipients of the study drug.