SHR-A1904 in Advanced Colorectal Cancer: an Exploratory Study

Inclusion Criteria:

1. Age 18-75 years, male or female.
2. Histologically or cytologically confirmed metastatic colorectal adenocarcinoma.
3. Failure of at least second-line standard systemic therapy, and must have received oxaliplatin, irinotecan, and fluoropyrimidine-based chemotherapy. Subjects who have received all three classes of chemotherapeutic agents in first-line therapy may be enrolled after first-line treatment failure. For subjects with dMMR/MSI-H tumors, prior anti-PD-1/PD-L1 antibody therapy must have failed.
4. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1.
6. Life expectancy ≥ 3 months.

7. Adequate major organ and bone marrow function before first dose of study drug, meeting the following criteria:

   1. Hematology (without transfusion, G-CSF or other medical support within 14 days before study drug administration): Hemoglobin ≥ 90 g/L; Platelets (PLT) ≥ 100×10^9/L; White blood cells (WBC) ≥ 3.5×10^9/L; Absolute neutrophil count (ANC) ≥ 1.5×10^9/L.
   2. Liver function: Total bilirubin (TBIL) ≤ 1.5×upper limit of normal (ULN); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5×ULN (in case of liver metastases, AST/ALT ≤ 5×ULN is permitted).
   3. Renal function: Creatinine ≤ 1.5×ULN or creatinine clearance ≥ 60 mL/min (calculated using the Cockcroft-Gault formula).
   4. Coagulation: International normalized ratio (INR) ≤ 1.5×ULN (or INR 2-3 for patients on stable long-term warfarin therapy), and activated partial thromboplastin time (aPTT) and prothrombin time (PT) ≤ 1.5×ULN.
8. Male patients and female patients of childbearing potential must agree to use adequate and effective contraception during the study and for 12 months after the last dose. Female patients must not be breastfeeding and must have a negative serum pregnancy test (β-hCG) within 7 days before the first dose.
9. Willing to voluntarily participate in this study, sign informed consent form, have good compliance, and cooperate with follow-up.

Exclusion Criteria:

1. Known history of hypersensitivity to any component of the investigational product.
2. Received systemic anti-tumor therapy within 4 weeks before the start of study treatment. If prior anti-tumor therapy was small molecule targeted therapy, the interval between the end of that treatment and the first study treatment should be no less than 5 half-lives of the drug or 7 days, whichever is longer. If prior anti-tumor Chinese patent medicine was received, an interval of no less than 2 weeks between the end of that treatment and the first study treatment is allowed.
3. Toxicities and/or complications from prior interventions have not recovered to NCI-CTCAE grade ≤1 or to the level specified in the inclusion/exclusion criteria (except for toxicities deemed by the investigator to be safely manageable, such as alopecia, grade ≤2 peripheral neuropathy, etc.).
4. Currently participating in another clinical study, or the time from first study drug administration to the end of a previous clinical study (last dose) is less than 4 weeks or 5 half-lives of that study drug, whichever is shorter.
5. Received treatment with strong inhibitors or inducers of CYP3A4, CYP2D6, P-gp, or BCRP within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose of study drug.
6. Major surgery within 28 days before the first dose of study treatment (major surgery refers to procedures requiring general anesthesia; at least 3 weeks of recovery time is required before study drug administration; tissue biopsy for diagnostic purposes is allowed).
7. Presence of another active malignancy other than the primary tumor (except for cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, superficial bladder cancer, ductal carcinoma in situ of the breast, papillary thyroid carcinoma, and gastrointestinal tumors confirmed to be cured by endoscopic mucosal resection). Patients with a history of prior malignancy (with disease cured for ≥2 years) may be enrolled.
8. Patients with untreated or active central nervous system (CNS) metastases or leptomeningeal metastases. If local treatment has been received and the patient's neurological symptoms have been stable for at least 2 weeks before the first dose, without requiring corticosteroids or requiring ≤10 mg/day prednisone (or equivalent), then participation is allowed.
9. Presence of serious complications of the primary tumor (e.g., perforation, obstruction, massive hemorrhage not manageable by medical therapy).
10. Uncontrolled or moderate to massive pleural effusion or pericardial effusion; clinically symptomatic moderate or severe ascites (i.e., requiring therapeutic paracentesis or drainage within 2 weeks before study treatment; patients with a small amount of ascites on imaging without clinical symptoms may be enrolled).
11. Uncontrolled hypertension or prior history of hypertensive crisis.
12. Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia requiring clinical intervention, second- or third-degree atrioventricular block, etc. Occurrence of acute coronary syndrome, congestive heart failure (New York Heart Association [NYHA] functional class ≥II), aortic dissection, stroke, or other grade ≥3 cardiovascular or cerebrovascular events within 6 months before the first dose.
13. Presence of any significant clinical or laboratory abnormality that, in the investigator's judgment, would affect safety evaluation, such as uncontrolled diabetes mellitus, chronic kidney disease, thyroid dysfunction, poorly controlled hypercholesterolemia despite medication, etc.
14. Active pulmonary tuberculosis, or history of active pulmonary tuberculosis infection within ≤48 weeks prior to screening, regardless of treatment status.
15. History of interstitial lung disease, or imaging findings at screening suggestive of or cannot rule out interstitial lung disease; or other moderate to severe pulmonary diseases that significantly affect lung function.
16. Subjects with active hepatitis B or active hepatitis C.
17. History of immunodeficiency, including positive HIV test, other acquired or congenital immunodeficiency disorders, or history of organ transplantation.
18. Severe infection within 4 weeks before the first dose, including but not limited to bacteremia requiring hospitalization, severe pneumonia, etc. Active infection of CTCAE grade ≥2 requiring systemic antibiotic therapy within 2 weeks before the first dose.
19. Pregnant or breastfeeding women, or patients of childbearing potential (males or females with less than one year of amenorrhea) who are unwilling to use contraceptive measures.
20. Any other condition that, in the investigator's judgment, would increase the risk of study participation, interfere with the study results, or make the subject unsuitable for this study.