RC48 Plus Tislelizumab, Low-dose Capecitabine and Celecoxib for HER2-positive Metastatic Colorectal Cancer

Disitamab Vedotin Combined With Tislelizumab, Low-dose Capecitabine and Celecoxib as Salvage Therapy for HER2-positive Metastatic Colorectal Cancer: a Phase II Trial (DETECT)

As an established therapeutic target, HER2 is widely used in a variety of tumors, including breast cancer and gastric cancer, among which a variety of drugs, including trastuzumab, lapatinib and T-DM1, have been approved for the treatment of breast cancer and gastric cancer with HER2 amplification or overexpression. In colorectal cancer, HER2 as a target has also been focused in recent years.

Inclusion Criteria:

1. A voluntarily signed and dated informed consent must be obtained from the subject in accordance with regulations and institutional guidelines before performing any protocol-related procedures other than routine care;

2. Aged 18-75;

3. Patients with pathologically or cytologically confirmed adenocarcinoma of the colon or rectum with evidence of locally advanced lesions or metastases that could not be resected;

4. ECOG performance status score is 0-1;

5. Detection of HER2-positive tumor tissue at any time before screening; HER2 positive was defined as the presence of HER2 3+ positive staining in more than 50% of tumor cells on IHC. Or patients with a HER2 score of 2+ should also be tested by FISH: HER2/CEP17 ratio ≥2.0.

6. Appropriate organ function based on the following laboratory test values obtained during the screening period:

   Neutrophil count ≥1.5×109/L, platelet count ≥75×109/L, serum total bilirubin ≤ 1.5× upper normal limits, UNL), aspartate aminotransferase ≤ 2.5×UNL, alanine aminotransferase ≤ 2.5×UNL, serum creatinine ≤ 1.5×UNL;

7. Previous chemotherapy including oxaliplatin, irinotecan, and fluorouracil failed, including the following:

   Subjects using oxaliplatin as adjuvant therapy should have treatment progression within 6 months of completion of adjuvant therapy; Patients who refused standard chemotherapy because of unacceptable toxicity to treatment will be admitted to the study;

8. Previous or no previous anti-HER2-targeted therapy, disease progression or intolerable toxicity during or within 3 months after treatment;

9. Measurable lesions, according to the Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1;

Exclusion Criteria:

1. Complicated with intestinal obstruction, active bleeding or perforation and requiring emergency surgery;
2. Major surgery or severe trauma, such as laparotomy, thoracotomy, laparoscopic organ resection, etc. within the previous 4 weeks (the surgical incision should be completely healed before enrollment);
3. Had active coronary artery disease, severe/unstable angina pectoris or newly diagnosed angina pectoris or myocardial infarction in the 12 months prior to study enrollment;
4. Thrombotic or embolic events occurred within the previous 6 months, such as cerebrovascular accident (including transient ischemic attack), pulmonary embolism, deep vein thrombosis;
5. The New York Heart Association (NYHA) class II or higher congestive Heart failure;
6. Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS), untreated active hepatitis (hepatitis B, defined as HBV-DNA ≥ 500 IU/ml; Hepatitis C, defined as HCV-RNA above the detection limit of the assay) or co-infection with hepatitis B and C;
7. The presence of any active, known or suspected autoimmune disease. To allow enrollment of subjects in stable condition who do not require systemic immunosuppressive therapy, such as type I diabetes, hypothyroidism that requires only hormone replacement therapy, and skin conditions that do not require systemic treatment (e.g., vitiligo, psoriasis, and alopecia);
8. The presence of interstitial lung disease, non-infectious pneumonia, or uncontrolled systemic diseases (e.g., diabetes mellitus, hypertension, pulmonary fibrosis, and acute pneumonia);
9. Common Terminology Criteria for Adverse events that have not resolved due to any previous treatment CTCAE) (version 5.0) grade 2 or higher toxicity (except peripheral neurotoxicity, anemia, alopecia, skin pigmentation);
10. Previous recipients of PD-1/PD-L1 inhibitors or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies;
11. A history of known or suspected allergies to any of the relevant drugs used in the study;
12. Pregnant or lactating women.