Optimizing immunotherapy with pre-surgery chemotherapy and radiation for locally advanced rectal cancer

A Prospective, Multicenter, Randomized Clinical Trial of Optimizing Immunotherapy Combined With Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer (STELLARIII)

This trial will test whether adding the immunotherapy drug sintilimab to different timings and types of pre-surgery chemotherapy and radiotherapy helps people with locally advanced rectal cancer shrink tumors and preserve rectal function.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 228 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy, radiation, prednisone
• Locations: 2 sites (Beijing and 1 other locations)
• Trial ID: NCT07040098 on ClinicalTrials.gov

What this trial studies

This phase 2 interventional trial compares different ways of combining the PD-1 inhibitor sintilimab with total neoadjuvant therapy (TNT) for clinical stage II/III rectal adenocarcinoma that is microsatellite-stable (MSS) or mismatch-repair proficient (pMMR). The study varies the timing of radiotherapy versus chemotherapy, the number of chemotherapy cycles (CAPOX), and the radiotherapy approach (short-course vs long-course concurrent chemoradiotherapy) alongside immunotherapy to find an optimal regimen. Participants receive preoperative systemic and local treatments intended to maximize tumor regression before planned surgery. Outcomes focus on tumor response rates and the potential for organ-preserving approaches.

Who should consider this trial

Good fit: Adults aged 18–75 with pathologically confirmed rectal adenocarcinoma staged II/III (cT2-4N0-2 without distant metastasis), pMMR or MSS status, ECOG 0–1, adequate labs, and no prior definitive rectal surgery are the intended participants.

Not a fit: Patients with distant metastatic disease, prior definitive pelvic surgery, significant comorbidities that preclude chemoradiation or immunotherapy, or non-MSS/dMMR tumors may not benefit from this specific approach.

Why it matters

Potential benefit: If successful, the approach could increase complete tumor responses and raise the chance of preserving rectal function without major surgery.

How similar studies have performed: Early-phase and retrospective reports have shown promising tumor regression when immune checkpoint inhibitors are added to neoadjuvant regimens, but published results are heterogeneous and high-quality evidence for pMMR/MSS rectal cancer remains limited.

Eligibility criteria

Inclusion Criteria:

1. Age 18-75 years, regardless of gender;
2. Pathologically confirmed rectal adenocarcinoma with immunohistochemical results indicating pMMR (proficient mismatch repair) or genetic testing confirming MSS (microsatellite stability);
3. Staged as clinical stage II/III (cT3-T4N0 or cT2-4N+, no distant metastasis, per the 8th Edition AJCC Cancer Staging Manual, 2018) via MRI or endoscopic ultrasound, and meeting any one of the following:

   * cT3 with tumor inferior margin ≤ 6 cm from the anal verge;

     * cT3c/d with tumor inferior margin ≥ 6-12 cm from the anal verge; ③ cN2; ④ cT4; ⑤ MRF+ (mesorectal fascia involvement); ⑥ EMVI+ (extramural vascular invasion);
4. ECOG performance status 0-1;
5. Meeting basic laboratory criteria (e.g., hematologic, hepatic, and renal function);
6. No history of hypersensitivity to 5-Fu-based agents or platinum-based drugs;
7. Patients with primary rectal cancer must have received no prior surgery (excluding palliative colostomy), chemotherapy, or other antitumor therapies from diagnosis to enrollment;
8. No prior radiation to the planned radiotherapy site;
9. Signed informed consent form.

Exclusion Criteria:

1. Prior treatment with anti-PD-1/L1 and/or anti-CTLA-4 immunotherapy or other investigational immunotherapeutic agents;
2. History of severe autoimmune diseases, including active inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (e.g., granulomatosis with polyangiitis);
3. Symptomatic interstitial lung disease or active infectious/non-infectious pneumonitis;
4. Risk factors for bowel perforation, such as active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal carcinomatosis, or other known predisposing conditions;
5. History of other malignancies, except for cured non-melanoma skin cancer or cervical carcinoma in situ;
6. Active infection, heart failure, myocardial infarction within 6 months, unstable angina, or uncontrolled arrhythmia;
7. Physical examination findings or clinical laboratory abnormalities deemed by the investigator to interfere with study outcomes or increase treatment-related risks, or other uncontrolled comorbidities;
8. Pregnant or breastfeeding women;
9. Congenital or acquired immunodeficiency disorders, including HIV infection, or history of organ/stem cell transplantation;
10. Active hepatitis B (HBV-DNA ≥2000 U/mL), hepatitis C (HCV), or active tuberculosis infection;
11. Prior administration of cancer vaccines or receipt of any vaccine within 4 weeks before treatment initiation (Note: Seasonal inactivated influenza vaccines are permitted; live-attenuated intranasal vaccines are prohibited);
12. Concurrent use of immunomodulators, chemotherapy, investigational drugs, or long-term corticosteroids (≥10 mg/day prednisone equivalent);
13. Patients with psychiatric disorders, substance abuse, or social circumstances that may compromise compliance, as assessed by the investigator;
14. Hypersensitivity or contraindications to the study medications.

Where this trial is running

Beijing and 1 other locations

• Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College — Beijing, China (Recruiting)
• National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen — Shenzhen, China (Recruiting)

Study contacts

• Study coordinator: Yuan Tang

Conditions Locally Advanced Rectal Cancer; Locally advanced rectal cancer; TNT; Immunotherapy; CR rate