Radiotherapy Combined With Capeox Chemotherapy, Sintilimab and Suvemcitug in Locally Advanced pMMR Rectal Cancer:a Prospective Clinical Trial

This study is a prospective, single-arm clinical trial with a dose-reduction design, which is expected to enrol 18 patients with locally advanced rectal cancer with pMMR status. The aim is to investigate the safety and efficacy of neoadjuvant chemoradiotherapy combined with sintilimab and suvecitib.

Patients will receive long-course chemoradiotherapy (concurrent capecitabine, 1000 mg/m², twice daily, days 1-14, Q3W, 2 cycles; sintilimab, 200 mg, d1, IV drip, Q3W, 2 cycles), followed by 6 cycles of the Capeox regimen in combination with sintilimab and suvecitib, namely oxaliplatin 130 mg/m², d1, IV infusion, every 3 weeks; and capecitabine 1,000 mg/m², twice daily, days 1-14, every 3 weeks; sintilimab, 200 mg, Day 1, IV drip, every 3 weeks; suvectitumab (anti-angiogenic agent), 2.0/1.5/1.0 mg/kg, Day 1, IV drip, every 3 weeks. A total of 8 cycles of sintilimab and 6 cycles of suvectitumab were administered during the neoadjuvant treatment period.

According to data from previous studies, the recommended dose of suvecitib in combination with a PD-L1 inhibitor and FOLFIRI chemotherapy for second-line treatment of advanced MSS colorectal cancer is 2 mg/kg every 2 weeks. However, given that the neoadjuvant treatment regimen in this clinical trial involves multiple modalities-including chemotherapy, radiotherapy, targeted therapy and immunotherapy-and the intensity is high with unknown toxicity profiles, a dose-escalation design was adopted in the early phase of this clinical study.

Specifically, six patients will initially be enrolled to receive suvicitabant at 2 mg/kg to assess safety. Following completion of neoadjuvant therapy in the third patient, if two or more patients develop Grade 4 acute radiation-induced rectal injury, the dose of suvicitabant will be reduced to 1.5 mg/kg for re-evaluation. If two or more patients still develop Grade 4 acute radiation-induced rectal injury, the dose will be further reduced to 1 mg/kg for re-evaluation.

If 1 or fewer patients develop Grade 4 acute radiation-induced rectal injury, the sample size for this cohort will be expanded to 18 patients. Following completion of neoadjuvant therapy, if a subject has not achieved cCR/near-cCR status, they will undergo TME or other therapeutic surgery; the interval between the final dose of suvecitib and surgery must be ≥6 weeks. If cCR/near-cCR status is achieved, watchful waiting or other treatment options will be discussed with the patient. Postoperatively, the investigator shall determine the adjuvant treatment regimen based on the patient's pathological results.

Inclusion criteria

• 1) Aged 18-75 years;

• ECOG 0-1;

• Histologically confirmed rectal adenocarcinoma;

• Preoperative staging: cT3-4N0M0 or cT1-4N+M0;

• Distance from the tumour's inferior margin to the anus ≤ 12 cm;

• Tumour biopsy immunohistochemistry indicates pMMR, i.e. positive expression of all MSH1/MSH2/MSH6/PMS2, and molecular testing indicates MSS (microsatellite-stable).

• Haematological parameters: WBC > 4,000/mm³; PLT > 100,000/mm³; Hb should, in principle, be > 10 g/dL; chronic anaemia (haemoglobin < 10.0 g/dL) is not an exclusion criterion and may be assessed by a multidisciplinary team;

• Liver function: Serum total bilirubin ≤ 1.5 × ULN (for subjects with Gilbert's syndrome, total bilirubin ≤ 3 × ULN is allowed)；aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN；

• Renal function: serum creatinine ≤ 1.5 × ULN, or creatinine clearance > 50 mL/min;

• Other: not pregnant or breastfeeding; no other malignant diseases within the past 5 years or concurrently (excluding basal cell carcinoma of the skin or cervical carcinoma in situ); no mental illness preventing the provision of informed consent; no concomitant serious diseases that would shorten survival;

• No previous surgery, chemotherapy or radiotherapy for rectal cancer;

• No previous immunotherapy;

• Previous endocrine therapy: no restrictions.

Exclusion criteria

• 1) Failure to sign an informed consent form;

• Immunohistochemistry of tumor biopsy specimens indicating dMMR or microsatellite instability testing indicating MSI-H;

• Preoperative evidence of distant metastasis;

• History of severe bleeding tendency or coagulation disorders; patients who have previously or currently require long-term anticoagulant therapy (e.g., patients with atrial fibrillation who have a CHADS2 score of ≥2).

• History of myocarditis, cardiomyopathy, or malignant arrhythmias. History of unstable angina, congestive heart failure, or vascular disease (e.g., an aortic aneurysm requiring surgical repair or peripheral venous thrombosis) requiring hospitalization within 12 months prior to study treatment, or other cardiac conditions that may affect the safety evaluation of the study drug (e.g., poorly controlled arrhythmias, myocardial infarction, or ischemia) ;

• History of esophageal or fundic varices, severe ulcers, unhealed wounds, gastrointestinal perforation, abdominal fistula, gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months prior to study treatment;

• History of any arterial thromboembolic event, venous thromboembolism of Grade 3 or higher according to NCI CTCAE Version 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 6 months prior to study treatment;

8)An acute exacerbation of chronic obstructive pulmonary disease (COPD) within 1 month prior to study treatment; current hypertension with a systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg despite treatment with oral antihypertensive medications; severe hypertension that is poorly controlled with medication;

• History of HIV infection or active chronic hepatitis B or C, or other active, clinically significant infections;

• Subjects with active pulmonary tuberculosis (TB) who are currently receiving antituberculosis therapy or who have received such therapy within 1 year prior to screening;

• Cachexia, organ dysfunction;

• History of pelvic or abdominal radiation therapy;

• Multiple primary colorectal cancers;

• Patients with seizures requiring treatment (e.g., with steroids or antiepileptic therapy);

• History of other malignancies within the past 5 years, excluding cured cervical carcinoma in situ or basal cell carcinoma of the skin;

• Substance abuse, or medical, psychological, or social conditions that may interfere with the patient's participation in the study or affect the evaluation of study results;

• Known or suspected allergy to the study drug or to any medication administered in connection with this trial;

• Any unstable condition or situation that may jeopardize the patient's safety or compliance;Pregnant or breastfeeding women of childbearing potential who are not using adequate contraception.