Umbrella Trial of Neoadjuvant Therapy for Locally Advanced Colorectal Cancer

An Exploratory Umbrella Trial of Neoadjuvant Therapy for Locally Advanced Colorectal Cancer Based on Molecular Subtypes

This is a prospective, open-label, single-center, phase II umbrella trial designed to evaluate the efficacy and safety of neoadjuvant therapy for locally advanced colorectal cancer. Patients will be stratified into four cohorts based on microsatellite instability (MSI) status, KRAS mutation status, and the consensus molecular subtypes (CMS). Six arms are included across four cohorts and each arm will be assigned to a specific treatment regimen. The primary endpoint is the complete response rate. Secondary endpoints include safety, organ preservation rate (for rectal cancer only), R0 resection rate, surgical complications, treatment compliance, 3-year survival, and quality of life (QoL) score.

Study Overview

• Status: Not yet recruiting
• Conditions: Locally Advanced Colorectal Cancer
• Intervention / Treatment: Drug: SHR-1701; Drug: SHR-8068; Radiation: Short-course radiotherapy; Drug: XELOX (Capecitabine and Oxaliplatin); Drug: PD-L1 antibody; Drug: HRS-7058; Drug: cetuximab β; Drug: HRS-4642

• Study Type: Interventional
• Enrollment (Estimated): 134
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhen Zhang; Phone Number: 18801735029; Email: zhen_zhang@fudan.edu.cn
• Study Contact Backup: Name: Shujuan Zhou; Phone Number: 18121297127; Email: zhoushujuan06@126.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age 18-75 years old, female and male;
2. Pathological confirmed adenocarcinoma;
3. Stage II/III colon cancer, or stage II/III rectal cancer located less than 10 cm from the anal verge;
4. Treatment-naïve and no distance metastases;
5. KPS ≥ 70;
6. No radiotherapy, chemotherapy, immunotherapy, or any other anti-tumor therapy had been administered prior to enrollment;
7. Baseline blood and biochemical indicators meet the following criteria: neutrophils ≥ 1.5 × 10^9/L, Hb ≥ 90 g/L, PLT ≥ 100 × 10^9/L, ALT/ AST ≤ 2.5 ULN, Cr ≤ 1 ULN;
8. With good compliance and signed the consent form.

Exclusion Criteria:

1. Pregnancy or breast-feeding women;
2. Known history of other malignancies within 5 years;
3. Known history of severe neurological or mental illness (such as schizophrenia, dementia or epilepsy);
4. Current severe cardiac disease (cardiac dysfunction and arrhythmia), renal dysfunction and liver dysfunction;
5. Acute cardiac infarction or cerebral ischemic stroke occurred within 6 months before recruitment;
6. Uncontrolled infection which needs systemic therapy;
7. Active autoimmune disease or immunodeficiencies, known history of organ transplantation or systematic use of immunosuppressive agents;
8. Known history of human immunodeficiency virus (HIV) infection (i.e., HIV 1 to 2 antibody positive), active syphilis infection, active pulmonary tuberculosis infection;
9. Allergic to any component of the therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MSI-H/dMMR	Drug: SHR-1701; 1800mg d1 q3w; Drug: SHR-8068; 280mg，C1D1
Experimental: MSS-KRAS G12C-Adebrelimab	Radiation: Short-course radiotherapy; 25Gy/5Fx; Drug: XELOX (Capecitabine and Oxaliplatin); Oxaliplatin: 130mg/m2 d1 q3w Capecitabine: 1000mg/m2 bid d1-14 q3w; Drug: PD-L1 antibody; 1200mg d1 q3w; Drug: HRS-7058; 200mg bid
Experimental: MSS-KRAS G12C-cetuximab β	Radiation: Short-course radiotherapy; 25Gy/5Fx; Drug: XELOX (Capecitabine and Oxaliplatin); Oxaliplatin: 130mg/m2 d1 q3w Capecitabine: 1000mg/m2 bid d1-14 q3w; Drug: HRS-7058; 200mg bid; Drug: cetuximab β; 250mg/m2 d1, 500mg/m2 d8 q3w
Experimental: MSS-KRAS G12D-Adebrelimab	Radiation: Short-course radiotherapy; 25Gy/5Fx; Drug: XELOX (Capecitabine and Oxaliplatin); Oxaliplatin: 130mg/m2 d1 q3w Capecitabine: 1000mg/m2 bid d1-14 q3w; Drug: PD-L1 antibody; 1200mg d1 q3w; Drug: HRS-4642; 500mg d1, 1200mg d8 q3w
Experimental: MSS-KRAS G12D-cetuximab β	Radiation: Short-course radiotherapy; 25Gy/5Fx; Drug: XELOX (Capecitabine and Oxaliplatin); Oxaliplatin: 130mg/m2 d1 q3w Capecitabine: 1000mg/m2 bid d1-14 q3w; Drug: cetuximab β; 250mg/m2 d1, 500mg/m2 d8 q3w; Drug: HRS-4642; 500mg d1, 1200mg d8 q3w
Experimental: MSS-CMS	Drug: SHR-1701; 1800mg d1 q3w; Radiation: Short-course radiotherapy; 25Gy/5Fx; Drug: XELOX (Capecitabine and Oxaliplatin); Oxaliplatin: 130mg/m2 d1 q3w Capecitabine: 1000mg/m2 bid d1-14 q3w

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Complete response (CR) rate: rate of complete response (CR), including the rate of pathologic complete response (pCR) after surgery and the rate of cCR with W&W strategy.	1 month after the surgery or 1 year after the decision of W&W.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse effects rate: proportion of participants with treatment-related adverse events as assessed by NCI-CTCAE v5.0.		From date of stratification to 3 months post-neoadjuvant therapy, an average of 8 months.
Organ preservation rate: proportion of participants who either achieve cCR and choose W&W or achieve cCR/near-cCR and choose local excision, out of the total participants who complete neoadjuvant therapy.	This endpoint is applicable only to patients with locally advanced rectal cancer.	From date of stratification until the resection of rectum or anus, assessed up to 36 months.
R0 resection rate: proportion of surgical resections with negative margins (proximal, distal, and circumferential) on microscopic examination, with CRM negativity defined as > 1 mm from tumor bed.		1 month after the surgery.
Rate of surgical complications: rates of surgical complications such as intraoperative hemorrhage, anastomotic leakage, intestinal obstruction, etc.		within 3 months after the surgery.
Treatment compliance: treatment completion rate and delay duration during the treatment period.		From date of stratification to the completion of neoadjuvant therapy, an average of 5 months.
3 year local recurrence free survival rate: proportion of participants with no tumor recurrence in the primary site (e.g., rectum) or other pelvic regions within 3 years from date of surgery or cCR.		From date of surgery or cCR until the date of first documented pelvic failure, assessed up to 36 months.
3 year distant metastasis free survival rate: proportion of participants with no distant metastases (e.g., liver, lung) within 3 years from date of stratification.		From date of stratification until the date of first documented distant metastasis, assessed up to 36 months.
3 year disease free survival rate: proportion of participants with no disease recurrence (including local recurrence and distant metastasis) or death from the disease within 3 years from date of stratification.		From date of stratification until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months.
3 year overall survival rate: proportion of participants who are alive at 3 years from date of stratification.		From date of stratification until the date of death from any cause, assessed up to 36 months.
Quality of life (QoL) score: subjective assessment using validated standardized questionnaires.		From date of stratification to 3 years post-neoadjuvant therapy.

Collaborators and Investigators

• Sponsor: Fudan University

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2030

Study Registration Dates

• First Submitted: March 20, 2026
• First Submitted That Met QC Criteria: March 25, 2026
• First Posted (Actual): March 31, 2026

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Uracil; Pyrimidinones; Deoxyribonucleosides; Fluorouracil; Capecitabine; Oxaliplatin; SHR-1701; XELOX
• Other Study ID Numbers: 2025-697-4846

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