A Multicenter, Randomized Controlled Phase II Study of Short-Course Radiotherapy Followed by Sequential PD-1 Inhibitor and FOLFOX Chemotherapy Versus Long-Course Chemoradiotherapy for High-Risk Locally Advanced pMMR/MSS Lower Rectal Adenocarcinoma (STAR Trial) (STAR)

This study adopts a prospective randomized controlled design to evaluate the efficacy and safety of short-course radiotherapy followed by sequential PD-1 inhibitor and FOLFOX chemotherapy versus conventional regimens in high-risk locally advanced pMMR/MSS lower rectal adenocarcinoma, aiming to provide high-level evidence supporting a novel treatment paradigm.

Study Overview

• Status: Recruiting
• Conditions: Immunotherapy; Rectal Adenocarcinoma; High-risk Locally Advanced; Short-course Radiotherapy (SCRT); FOLFOX
• Intervention / Treatment: Radiation: Short-course Radiotherapy, SCRT; Drug: Toripalimab

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangzhou, China
    • Recruiting
    • The sixth affiliated hospital of Sun Yat-Sen University
    • Contact: YiFeng Zou; Phone Number: 13719225862; Email: zouyif@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Before implementing any procedures related to the study protocol rather than routine clinical care, a signed and dated informed consent form must be obtained from the subject voluntarily, in accordance with regulatory requirements and institutional guidelines.
2. Age 18-75 years.
3. Histologically or cytologically confirmed pMMR/MSS rectal adenocarcinoma.
4. The lower edge of the rectal tumor is located below the peritoneal reflection.
5. Locally advanced disease with high-risk factors, meeting at least one of the following: cT4 / cN2 / EMVI+ / MRF+ / positive lateral lymph node.
6. No clear evidence of distant metastasis prior to treatment.
7. No prior anti-tumor therapy (radiotherapy, chemotherapy, targeted therapy, or immunotherapy).
8. ECOG performance status 0-1 (Appendix 1).

9. Peripheral blood counts and liver and renal function within the following ranges (tested within 15 days before treatment initiation):

   • White blood cell count (WBC) ≥ 3.0 × 10⁹/L or absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L;

     • Hemoglobin (HGB) ≥ 80 g/L; ③ Platelet count (PLT) ≥ 100 × 10⁹/L; ④ Hepatic transaminases (AST/ALT) < 3.0 × upper limit of normal (ULN); ⑤ Total bilirubin (TBIL) < 1.5 × ULN; ⑥ Creatinine (CREAT) < 1.5 × ULN.
10. No history of other concurrent malignancies; not pregnant or lactating; effective contraceptive methods should be used during the study period and for 6 months after the last dose.

Exclusion Criteria:

1. Patients with a history of severe drug allergy (including allergy to platinum agents, 5-FU, and 5-HT3 receptor antagonists).
2. Patients who have participated in or are currently participating in another clinical trial within 4 weeks prior to enrollment.
3. History of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, or any other therapy specifically targeting T-cell co-stimulation or checkpoint pathways.
4. Severe electrolyte abnormalities.
5. Presence of gastrointestinal diseases such as active gastric or duodenal ulcer, ulcerative colitis, or unresected tumor with active bleeding; or other conditions that may cause gastrointestinal bleeding or perforation; or unhealed gastrointestinal perforation after surgical treatment.
6. History of arterial thrombosis or deep vein thrombosis within 6 months; evidence of bleeding tendency or hemorrhagic history within 2 months; currently receiving high-dose anticoagulation therapy.
7. Pregnant or lactating women, or women of childbearing potential with a positive pregnancy test prior to the first dose; or female participants and their partners who are unwilling to practice strict contraception during the study period.
8. Presence of other concurrent or prior active malignancies (except for malignancies that have been curatively treated with no recurrence for more than 3 years, or carcinoma in situ that can be cured by adequate treatment).
9. Severe electrocardiogram abnormalities, or active coronary artery disease, severe/unstable angina, newly diagnosed angina or myocardial infarction within 12 months prior to study entry, or congestive heart failure of NYHA Class II or higher.
10. Patients with active infection (infection causing fever > 38°C).
11. Patients with poorly controlled hypercalcemia, hypertension, or diabetes mellitus.
12. Patients with severe pulmonary disease (interstitial pneumonia, pulmonary fibrosis, severe emphysema, etc.).
13. Patients with mental disorders affecting clinical treatment or a history of central nervous system disease.
14. Patients with severe complications (intestinal obstruction, renal insufficiency, hepatic insufficiency, cerebrovascular disorders, etc.).
15. Presence of any unresolved toxicity of CTCAE Grade 2 or higher resulting from prior therapy (except for anemia, alopecia, and skin pigmentation).
16. Any medical condition that is unstable or may affect patient safety and compliance with the study.
17. Patients deemed by the investigator to be unsuitable for participation in this clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SCRT-PD1-FOLFOX	Radiation: Short-course Radiotherapy, SCRT; The neoadjuvant treatment phase includes either SCRT followed by 6 cycles of FOLFOX chemotherapy combined with a PD-1 inhibitor, or LCRT concurrent with 6 cycles of FOLFOX chemotherapy. Surgery is performed 2-4 weeks after the last cycle of chemotherapy. If reassessment indicates cCR and N0, options include Total Mesorectal Excision (TME), local excision (LE), or watch and wait (W&W); otherwise, TME is performed. Postoperative adjuvant chemotherapy follows the CAPOX regimen.; Drug: Toripalimab; The neoadjuvant treatment phase includes either SCRT followed by 6 cycles of FOLFOX chemotherapy combined with a PD-1 inhibitor, or LCRT concurrent with 6 cycles of FOLFOX chemotherapy. Surgery is performed 2-4 weeks after the last cycle of chemotherapy. If reassessment indicates cCR and N0, options include Total Mesorectal Excision (TME), local excision (LE), or watch and wait (W&W); otherwise, TME is performed. Postoperative adjuvant chemotherapy follows the CAPOX regimen.
Active Comparator: LCRT-FOLFOX	Radiation: Short-course Radiotherapy, SCRT; The neoadjuvant treatment phase includes either SCRT followed by 6 cycles of FOLFOX chemotherapy combined with a PD-1 inhibitor, or LCRT concurrent with 6 cycles of FOLFOX chemotherapy. Surgery is performed 2-4 weeks after the last cycle of chemotherapy. If reassessment indicates cCR and N0, options include Total Mesorectal Excision (TME), local excision (LE), or watch and wait (W&W); otherwise, TME is performed. Postoperative adjuvant chemotherapy follows the CAPOX regimen.; Drug: Toripalimab; The neoadjuvant treatment phase includes either SCRT followed by 6 cycles of FOLFOX chemotherapy combined with a PD-1 inhibitor, or LCRT concurrent with 6 cycles of FOLFOX chemotherapy. Surgery is performed 2-4 weeks after the last cycle of chemotherapy. If reassessment indicates cCR and N0, options include Total Mesorectal Excision (TME), local excision (LE), or watch and wait (W&W); otherwise, TME is performed. Postoperative adjuvant chemotherapy follows the CAPOX regimen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CCR	cCR+pCR	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
3-year RFS	3 years
3-year DFS	3 years
3-year OS	3 years
3-year DMFS	3 years
R0 Resection Rate	3 years
MPR Rate	3 years
Treatment-Related Adverse Events / Treatment Toxicity	3 years

Collaborators and Investigators

• Sponsor: Sixth Affiliated Hospital, Sun Yat-sen University
• Collaborators: Junshi Biosciences

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2026
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: June 21, 2026
• First Submitted That Met QC Criteria: June 21, 2026
• First Posted (Actual): June 25, 2026

Study Record Updates

• Last Update Posted (Actual): June 25, 2026
• Last Update Submitted That Met QC Criteria: June 21, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Rectal Neoplasms; toripalimab
• Other Study ID Numbers: 2026ZSLYEC-285

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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