Short-Course Online Adaptive Radiotherapy Combined With Chemotherapy, Targeted Therapy and Immunotherapy as Total Neoadjuvant Therapy (TNT) for Locally Advanced Rectal Cancer

A Single-Arm, Phase 2 Clinical Study on the Efficacy and Safety of Short-Course Online Adaptive Radiotherapy Combined With Chemotherapy, Targeted Therapy and Immunotherapy as Total Neoadjuvant Therapy (TNT) for Locally Advanced Rectal Cancer

Standard treatment for patients with proficient mismatch repair (pMMR) / microsatellite stable (MSS) locally advanced rectal cancer (LARC) consists primarily of neoadjuvant chemoradiotherapy followed by radical surgery. Several studies (including the UNION, STELLAR, TORCH, and SPRING-01 trials, etc) have demonstrated that the neoadjuvant strategy of short-course radiotherapy followed by chemotherapy combined with immunotherapy can improve pCR rate in patients with pMMR/MSS LARC, and might also provide higher organ preservation rates and long-term survival benefits. The study aims to explore the efficacy and safety of a TNT regimen comprising short-course radiotherapy combined with chemotherapy, cetuximab N01 (for patients with wild-type RAS/BRAF) or bevacizumab (for patients with mutant RAS/BRAF), and sintilimab in patients with high-risk LARC.

Study Overview

• Status: Not yet recruiting
• Conditions: Locally Advanced Rectal Cancer (LARC)
• Intervention / Treatment: Drug: SCRT+targeted therapy+immunotherapy+chemotherapy

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Guanghai Dai, MD; Phone Number: +86 13801232381; Email: 463043539@qq.com

Study Locations

• China
  • Beijing, China
    • China PLAGH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Voluntarily signed the informed consent form.
• Aged 18-75 years (inclusive of 18 and 75 years).
• pMMR/MSS.
• Middle or low rectal cancer located ≤10 cm from the anal verge as assessed by MRI.
• Histopathologically confirmed locally advanced rectal adenocarcinoma and high-risk features confirmed by pelvic MRI (meeting any of the following criteria: clinical stage cT3N+ or cT4N0/+; MRF+ or EMVI+; enlarged lateral pelvic lymph nodes).
• ECOG PS of 0-1.
• Expected survival ≥2 years.
• No prior anti-tumor therapy.
• At least one measurable lesion with a longest diameter ≥10 mm measured by MRI (by RECIST version 1.1).
• Organ functions meeting the following requirements (no blood products or cell growth factors allowed within 14 days prior to enrollment):

Absolute neutrophil count ≥1.5×10⁹/L; Platelet count ≥100×10⁹/L; Hemoglobin ≥90 g/L; Total bilirubin <1.5×ULN; ALT and/or AST <2.5×ULN; Serum creatinine <1.5×ULN; Creatinine clearance ≥50 mL/min.

• Women of childbearing potential must use effective contraceptive measures.
• Good compliance and willingness to comply with follow-up requirements.

Exclusion Criteria:

• Unable to comply with the study protocol or study procedures.
• Patients with contraindications to surgery.
• Patients with metastatic disease or recurrent rectal cancer.
• Uncontrolled active autoimmune disease or active inflammatory disease at enrollment, or receiving immunosuppressive therapy.
• History of organ transplantation.
• Known interstitial lung disease (ILD) or unexplained persistent cough and dyspnea.
• Patients with familial adenomatous polyposis (FAP), hereditary non-polyposis colorectal cancer (HNPCC), active Crohn's disease, or active ulcerative colitis.
• Other malignancy diagnosed within 5 years prior to enrollment, except for radically resected basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
• Severe cardiovascular disease within 6 months prior to enrollment, including unstable angina pectoris or myocardial infarction.
• Subjects with hypersensitivity to the investigational product or any of its excipients.
• Participation in another clinical trial of an unapproved/investigational drug within 4 weeks prior to enrollment and having received the corresponding investigational product.
• Clinically significant electrolyte abnormalities judged by the investigator.
• Uncontrolled hypertension prior to enrollment, defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg despite medication.
• Poorly controlled diabetes mellitus prior to enrollment (fasting glucose concentration ≥ CTCAE Grade 2 after standard treatment).
• Any disease or condition affecting drug absorption prior to enrollment, or inability of the patient to take oral medication.
• Active gastrointestinal diseases such as gastric and duodenal ulcer, ulcerative colitis prior to enrollment, or other conditions judged by the investigator that may cause gastrointestinal bleeding or perforation.
• Severe active bleeding within 3 months prior to enrollment, hemoptysis (>5 mL fresh blood within 4 weeks), or thromboembolic event (including stroke and/or transient ischemic attack) within 12 months.
• Clinically significant cardiovascular disease including but not limited to: acute myocardial infarction, severe/unstable angina pectoris, or coronary artery bypass grafting within 6 months prior to enrollment; congestive heart failure with New York Heart Association (NYHA) classification > Grade 2; ventricular arrhythmia requiring pharmacotherapy; left ventricular ejection fraction (LVEF) < 50%.
• Active or uncontrolled severe infection (≥ CTCAE v5.0 Grade 2).
• Known human immunodeficiency virus (HIV) infection. Known clinically significant liver disease history, including viral hepatitis:
• Hepatitis B virus (HBV) carriers with active HBV infection (HBV DNA positive: >1×10⁴ copies/mL or >2000 IU/mL);
• Known hepatitis C virus (HCV) infection with positive HCV RNA (>1×10³ copies/mL).
• Unresolved toxicities higher than CTCAE v5.0 Grade 1 resulting from any prior anti-cancer therapy, excluding alopecia, lymphopenia, and oxaliplatin-induced neurotoxicity ≤ Grade 2.
• Female subjects who are pregnant (positive pregnancy test before treatment) or breastfeeding.
• Urinalysis showing urine protein ≥ 2+ and 24-hour urinary protein > 1.0 g.
• Any other disease, clinically significant metabolic abnormality, physical examination abnormality, or laboratory abnormality that, in the investigator's judgment, renders the patient unsuitable for the study drug (e.g., seizure disorder requiring treatment), interferes with the interpretation of study results, or places the patient at high risk.
• Patients considered unsuitable for inclusion in this study by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: SCRT+Sintilimab+Cetuximab N01/Bevacizumab+mFOLFOX6/CAPOX

Drug: SCRT+targeted therapy+immunotherapy+chemotherapy; SCRT: 25 Gy, 5 Gy × 5 fr. One week after completion of SCRT: Patients with wild-type RAS/BRAF:mFOLFOX6: oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-fluorouracil 400 mg/m² IV bolus on Day 1; followed by 5-fluorouracil 2400 mg/m² continuous infusion over 46 hours, q2w; sintilimab 200 mg/m² IV infusion on Day 1, q3w; cetuximab N01 500 mg/m² IV infusion on Day 1, q2w; Combination therapy for 18 weeks (9 cycles of chemotherapy).; Patients with mutant RAS/BRAF: CAPOX: oxaliplatin 130 mg/m² IV ivgtt, D1; capecitabine 1000 mg/m² BID, po, D1-14, q3w, for 6 cycles; sintilimab 200 mg/m² ivgtt, D1, q3w, for 6 cycles; bevacizumab 7.5 mg/kg IV infusion on Day 1, q3w, for 5 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR)	CR = Pathological Complete Response (pCR) + Clinical Complete Response (cCR)	Within 3 months after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 resection rate	Proportion of patients achieving a margin-negative tumor removal	Within 3 months after surgery
LER	Local Excision rate	Within 3 months after surgery
ORR	Objective Response Rate of neoadjuvant therapy ( by RECIST 1.1)	Around 6 months after recruitment
DCR	Disease Control Rate of neoadjuvant therapy (by RECIST 1.1)	Around 6 months after recruitment
3y-EFS	3 years events-free survival	Around 3 years after recruitment
3y-RFS	3 years recurrence-free Survival	Around 3 years after recruitment
OS	Overall Survival	Around 5 years after recruitment
Safety Measures	Incidence and grades of treatment related adverse events (by NCI-CTCAE 5.0) and surgery related safeties	Within 3 months after surgery

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: April 21, 2026
• First Submitted That Met QC Criteria: May 5, 2026
• First Posted (Actual): May 12, 2026

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 14, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: KL-A140-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No