Neoadjuvant Iparomlimab/Tuvonralimab Plus CAPEOX Versus Iparomlimab/Tuvonralimab Plus CAPEOX and Propranolol for Locally Advanced pMMR Colon Cancer: A Prospective, Single-Center, Multi-Cohort Study

Prior treatment

• Any of the following complications:
  • Major GI bleeding, perforation, or GI obstruction (including paralytic ileus)
  • Symptomatic heart disease (including unstable angina, myocardial infarction, heart failure)
  • Uncontrolled diabetes, hypertension, or hypotension
  • Uncontrolled diarrhea that interferes with daily activities despite adequate treatment
  • Use of immunosuppressants or systemic/absorbable local steroids for immunosuppression (\>10 mg/day prednisone equivalent) and still using within 2 weeks before enrollment
• Prior or current thyroid dysfunction that cannot be maintained within normal range despite medication.
• Use of traditional Chinese immune modulators within 2 weeks before treatment, or receipt of systemic anti-tumor therapy (chemotherapy, immunotherapy, biologic therapy, etc.) or TCM anti-tumor therapy within 4 weeks before treatment.
• Receipt of a live vaccine within 4 weeks prior to study drug or anticipated need for live vaccination during the study.
• Definite history of hypertension (without antihypertensives: non-same-day 3 measurements with SBP ≥140 mmHg and/or DBP ≥100 mmHg, or currently receiving antihypertensive therapy).

Other illness

• History of allergic disease, severe drug allergy, known allergy to macromolecular protein products, or allergy to Iparomlimab/Tuvonralimab (protocol wording originally referenced the Chinese drug name).
• Cardiopulmonary insufficiency or hepatic/renal insufficiency such that CAPEOX cannot be tolerated; known allergy to oxaliplatin or capecitabine.
• Poorly controlled cardiac symptoms or clinically significant heart disease, including:
  • NYHA class \>II heart failure
  • Unstable angina
  • Myocardial infarction within 1 year
  • Clinically significant supraventricular or ventricular arrhythmia requiring treatment/intervention
• Active infection, or unexplained fever \>38.5°C during screening or before first dose (tumor-related fever may be allowed per investigator judgment).
• History or current objective evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, known active pulmonary tuberculosis, severely impaired lung function, etc.
• Congenital or acquired immunodeficiency, e.g., HIV infection (HIV 1/2 antibody positive).
• Acute or chronic active HCV: HCV antibody positive and HCV RNA above LLOD.
• Known history of psychoactive substance abuse, alcoholism, or drug abuse.
• History of allergy to β-blockers.
• Asthma, COPD, or other respiratory disease requiring bronchodilator therapy.
• Clear history of hypotension; baseline SBP \<90 mmHg or DBP \<60 mmHg.
• Any other condition judged by the investigator to warrant exclusion (e.g., factors that may force early termination of study participation).

Lab values

• Acute or chronic active HBV: HBsAg(+) or HBcAb(+) requires HBV DNA testing. Eligible only if HBV DNA \<2×10³ copies/mL or \<200 IU/mL or below LLOD; HBsAg(+) must receive anti-HBV therapy during study treatment; HBcAb(+)/HBsAg(-)/anti-HBs(-) with negative viral load does not require prophylaxis but requires close monitoring.

Other

• Participants meeting any of the following are excluded:
• Presence of distant metastasis.
• Pregnant or breastfeeding women, or men/women unwilling to use contraception.

• Participants must meet all of the following:
• Diagnosis / Stage: Histologically confirmed and radiologically assessed colon adenocarcinoma that is T4, or T3 with lymph node metastasis, with tumor location ≥10 cm from the anal verge, and clinical TNM staging per AJCC/UICC 8th edition.
• Measurable disease: At least one measurable lesion per RECIST v1.1 (non-lymph node lesion long axis ≥10 mm on CT; lymph node lesion short axis ≥15 mm on CT).
• pMMR/MSS confirmation: pMMR by IHC on colonoscopy biopsy (MMR proteins by immunohistochemistry), or MSS/MSS-L by PCR or NGS.
• Treatment-naïve for current colon cancer: No prior anti-tumor treatment for colon cancer. (If Lynch syndrome, no anti-tumor treatment for the current diagnosis.)
• Age: 18 to 75 years, any sex.
• Performance status / organ function: ECOG 0-1 with adequate organ and bone marrow function.
• Informed consent: Written informed consent signed before enrollment.
• Life expectancy: Expected survival \>12 weeks.
• Hematology and chemistry (without blood products or growth factors within 14 days):
  • Hemoglobin ≥60 g/L
  • ANC ≥1.5 × 10⁹/L
  • Platelets ≥75 × 10⁹/L
  • Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min (Cockcroft-Gault)
  • Total bilirubin ≤1.5 × ULN
  • AST or ALT ≤2.5 × ULN (if abnormal due to liver metastasis, ≤5 × ULN)
  • Urine protein \<2+; if ≥2+, 24-hour urine protein ≤1 g
• Coagulation / bleeding-thrombosis status: No active bleeding and no thrombotic disease; patients may be eligible if thrombosis is treated and stable for ≥3 months. Must meet:
  • INR ≤1.5 × ULN
  • APTT ≤1.5 × ULN
  • PT ≤1.5 × ULN
• Thyroid function within normal range:
  • Free T4 12-22 pmol/L
  • Free T3 2.8-7.1 pmol/L
  • TSH 0.27-4.2 mIU/L
• Blood pressure requirement (screening): Average seated BP 100-150 / 60-90 mmHg, and 24-hour ambulatory BP below the threshold for Grade I hypertension.
• Contraception / pregnancy test (for women of childbearing potential): Must use medically approved contraception during treatment and for 3 months after; pregnancy test (serum or urine HCG negative within 7 days prior to enrollment); not breastfeeding.
• Compliance: Willing and able to comply with study procedures and safety/survival follow-up.