A Phase II Study of Pirfenidone Plus PD-1 Inhibitor With or Without Hypofractionated Radiotherapy for Refractory pMMR/MSS Colorectal Cancer

Exclusion Criteria

• •1. All colorectal cancer patients must have confirmed MSS/pMMR status; patients with MSI-H/dMMR are excluded.
• •2. History of hypersensitivity to any study drug components, including PD-1 inhibitors and pirfenidone.
• •3. Female patients who are pregnant, lactating, or planning to become pregnant within 6 months after the last dose of the study drug.
• •4. Known history or presence of active seizure disorder, active central nervous system metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease. Patients with newly identified brain or leptomeningeal metastases are excluded.
• •5. Significant cardiovascular or cerebrovascular diseases with clinical importance.
• •6. History of allergic predisposition, asthma, or atopic dermatitis.
• •7. Patients with massive pleural effusion or massive ascites.
• •8. Active autoimmune disease requiring systemic treatment (e.g., disease-modifying agents, corticosteroids, or immunosuppressants) within the past 2 years prior to the first dose. Replacement therapy is not considered systemic treatment.
• •9. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• •10. Known or suspected hypersensitivity to the study drugs or any of their excipients.
• •11. History of significant toxicity related to prior immune checkpoint inhibitor therapy or pirfenidone treatment that led to permanent discontinuation of the drug.
• •12. Presence of unresolved \> Grade 1 toxicities (except for persistent Grade 2 alopecia, peripheral neuropathy, decreased hemoglobin, or hypomagnesemia) from any prior anticancer therapy.
• •13. Active uncontrolled bleeding, known bleeding tendency, severe non-healing wounds, ulcers, fractures, or conditions such as esophageal/gastric varices requiring immediate intervention, or portal hypertension with high bleeding risk per investigator's assessment.
• •14. History of intestinal obstruction (except if surgically cured or fully resolved) or risk of gastrointestinal perforation within 28 days prior to the first study dose.
• •15. Current or recent (within 6 months) significant gastrointestinal disorders, including:
• •1. History of clinically significant GI bleeding,
• •2. Active peptic ulcer disease,
• •3. ≥ Grade 2 diarrhea within 2 weeks prior to the first study dose.
• •16. Gastrointestinal diseases or prior surgeries that may affect the absorption of oral pirfenidone; uncontrolled tumor-related pain or symptomatic hypercalcemia.
• •17. Known positive HIV status, active Hepatitis B, Hepatitis C, tuberculosis, or history of such infections. Exceptions include:
• •* Patients positive for HBsAg or HBcAb with HBV DNA ≤ 2.5×10³ copies/mL or ≤ 500 IU/mL or below the detection limit.
• •* Patients with positive HCV serology but undetectable HCV RNA.
• •* Patients who have received HCV treatment with undetectable viral load.
• •18. Severe/active/uncontrolled infection, infection requiring IV antibiotics, or unexplained fever (\>38°C) within 2 weeks prior to the first study dose.
• •19. Diagnosis of another malignancy within 5 years prior to the first dose, with exceptions for adequately treated basal cell carcinoma, squamous cell carcinoma, carcinoma in situ, or localized prostate/thyroid cancer treated with curative intent.
• •20. Prohibited treatments prior to enrollment:
• •* Chemotherapy or small-molecule targeted therapy within 2 weeks or 5 half-lives (whichever is shorter) before the first study dose, with unresolved delayed toxicity.
• •* Monoclonal antibody therapy within 4 weeks prior to the first study dose.
• •* Participation in any interventional clinical trial involving medical devices or other therapies within 2 weeks prior to the first study dose.
• •* Palliative radiotherapy within 2 weeks prior to the first study dose.
• •* Live vaccines for infectious disease prevention within 4 weeks prior to the first study dose.
• •* Immunosuppressive or systemic steroid therapy (\>10 mg/day prednisone equivalent) within 2 weeks prior to the first study dose.
• •* Unstable anticoagulation control, thrombotic events, pulmonary embolism, or clinically significant bleeding within 6 months.
• •* Major surgery within 4 weeks prior to the first study dose.
• •21. Any condition, therapy, laboratory abnormality, history of substance abuse, or current situation that may compromise patient safety, interfere with informed consent, affect compliance, or confound safety assessment of the study drug per investigator's judgment.
• •22. Patients deemed unsuitable for clinical trial participation by the investigator.