Colorectal Cancer (CRC)
Conditions
Brief summary
This study aims to evaluate the safety, tolerability, and efficacy of pirfenidone and PD-1 monoclonal antibody combined with or without hypofractionated radiotherapy in the treatment of advanced refractory pMMR/MSS colorectal cancer patients.
Interventions
DRUGPirfenidone in combination with a PD-1 inhibitor
The PD-1 inhibitor will be administered intravenously at 200 mg every 3 weeks. Pirfenidone dosing will follow an escalating regimen: 200 mg orally three times daily, 400 mg orally three times daily, and 600 mg orally three times daily.
RADIATIONhypofractionated radiotherapy
hypofractionated radiotherapy
Sponsors
Tao Zhang
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent must be provided, and the patient must be able to comply with the visit schedule and procedures outlined in the protocol. 2. Age ≥ 18 years and ≤ 75 years, regardless of gender. 3. Histologically or cytologically confirmed, unresectable locally advanced or metastatic pMMR/MSS colorectal cancer. 4. Patients must have progressed on standard therapy, be unsuitable for standard therapy due to intolerable toxicity, have no available standard therapy, or have refused standard therapy. 5. Baseline\* hematology tests (within 7 days prior to the first dose of study drug) must meet the following criteria:Hemoglobin ≥ 90 g/L (without transfusion or erythropoietin support within 7 days prior to blood sampling). Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L (without granulocyte colony-stimulating factor support within 7 days prior to blood sampling).Platelet count ≥ 100 × 10⁹/L (without transfusion support within 7 days prior to blood sampling).Eosinophil count ≤ 1.5 × ULN. 9.Throughout the protocol, "baseline" is defined as the last available observation prior to the first dose of the study drug. Patients must not have received any blood products or hematopoietic growth factor support within 7 days prior to the blood sample collection. 10.Baseline serum biochemistry tests (within 7 days prior to the first dose) must meet the following criteria:Total bilirubin ≤ 1.5 × ULN (if total bilirubin is \>1.5 × ULN, direct bilirubin must be ≤ ULN for inclusion).Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3 × ULN. Serum creatinine ≤ 1.5 × ULN or Calculated Creatinine Clearance (CrCl) ≥ 45 mL/min (using the Cockcroft-Gault formula and actual body weight).Albumin ≥ 30 g/L. 11.Baseline coagulation tests (within 7 days prior to the first dose) must meet the following criteria:International Normalized Ratio (INR) ≤ 1.5 × ULN (or ≤ 3 × ULN if on a stable dose of anticoagulant therapy).Partial Thromboplastin Time (PTT) or Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN (or ≤ 3 × ULN if on a stable dose of anticoagulant therapy). 12.Baseline urinalysis (within 7 days prior to the first dose) must meet the following criterion: Urine Protein (UPRO) \< 2+ or 24-hour urinary protein quantification \< 1 g. 13.At least one measurable lesion as defined by RECIST v1.1 criteria. 14.Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. 15.Life expectancy ≥ 3 months. 16.Male patients with partners of reproductive potential and female patients of childbearing potential must agree to use highly effective contraception throughout the treatment period and for 6 months thereafter.
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival（PFS） | an expected average of 6 months | Progression-free survival (PFS) is defined as the time from the initiation of study treatment to the first occurrence of disease progression or death from any cause, whichever comes first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | an expected average of 5 years | The time from the date of randomization to the death caused by any cause |
| Objective Response Rate | an expected average of 2 years | The proportion of patients in a study cohort whose best overall response achieves either a complete response (CR) or a partial response (PR), as defined by standardized oncologic criteria (such as RECIST 1.1), during the course of the treatment period. |
| dverse events (AEs) were graded according to the NCI CTCAE version 5·0 | an expected average of 1.5 years | Adverse events and surgical safety |
Countries
China
Contacts
CONTACTZhenyu Lin, MD
PRINCIPAL_INVESTIGATORTao Zhang, MD
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Outcome results
None listed