Short-course Radiotherapy Combined With Retlirafusp Alfa and CAPOX Chemotherapy as Neoadjuvant Therapy for Locally Advanced Rectal Cancer: A Prospective, Single-arm, Phase II Clinical Study

This study aims to evaluate the efficacy and safety of neoadjuvant short-course radiotherapy combined with Retlirafusp alfa and CAPOX chemotherapy in the treatment of locally advanced rectal cancer. This is a prospective, single-arm, phase II clinical trial planned to enroll 44 patients with locally advanced rectal cancer. The primary endpoint is the complete response rate, and secondary endpoints include objective response rate, pathological complete response rate, event-free survival, and overall survival, with the goal of providing evidence to optimize clinical treatment decisions.

Study Overview

• Status: Active, not recruiting
• Conditions: Rectal Cancer Patients
• Intervention / Treatment: Drug: Short-course radiotherapy combined with Retlirafusp alfa and CAPOX chemotherapy

Detailed Description

The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy followed by total mesorectal excision. However, the pathological complete response rate of the traditional regimen is only 10%-15%, and the distant metastasis rate remains high, which falls short of clinical needs. In recent years, immune checkpoint inhibitors have demonstrated significant efficacy in various malignancies. However, microsatellite-stable (MSS) colorectal cancer responds poorly to immunotherapy monotherapy and is therefore considered a "cold tumor." Preclinical and clinical studies suggest that radiotherapy can enhance immune responses by remodeling the tumor microenvironment and promoting tumor antigen release, thereby exerting synergistic antitumor effects when combined with immunotherapy. In addition, the TGF-β signaling pathway plays an important role in immune evasion in colorectal cancer, and bifunctional fusion proteins that simultaneously target PD-L1 and TGF-β are expected to more effectively restore T-cell activity. Based on these findings, this study innovatively combines short-course radiotherapy, Retlirafusp alfa (an anti-PD-L1/TGF-βRII bifunctional fusion protein), and the CAPOX chemotherapy regimen as neoadjuvant therapy for locally advanced rectal cancer.This study plans to enroll 44 patients with previously untreated locally advanced rectal cancer (T3N+M0 or T4NanyM0, AJCC 8th edition). The treatment regimen consists of short-course radiotherapy (25 Gy/5 fractions, D2-D6) combined with Retlirafusp alfa and CAPOX chemotherapy in the first cycle, followed by Retlirafusp alfa plus CAPOX chemotherapy in cycles 2 through 4. Efficacy evaluations will be performed after cycles 2 and 4, respectively. Patients who achieve clinical complete response may opt for a watch-and-wait strategy, while those who do not are recommended to undergo total mesorectal excision. The primary endpoint is the complete response rate (cCR + pCR). Secondary endpoints include objective response rate, pathological complete response rate, major pathological response, tumor regression grade,event-free survival, overall survival, safety, and changes in patient quality of life and anal function. The conduct of this study will provide important evidence on the efficacy and safety of the "short-course radiotherapy + immunotherapy + chemotherapy" neoadjuvant treatment model for locally advanced rectal cancer, with the potential to offer patients greater opportunities for organ preservation and improved long term survival.

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150081
      • Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, Heilongjiang Province, China

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age 18-70 years, male or female.
2. Histologically or cytologically confirmed rectal adenocarcinoma, stage T3N+M0 or T4NanyM0 (AJCC/UICC TNM 8th edition), with measurable lesion(s) per RECIST 1.1.
3. Tumor lower border 5-10 cm from the anal verge.
4. Expected to achieve R0 resection after neoadjuvant therapy, and planned for surgery thereafter.
5. ECOG PS 0-1.
6. No prior anti-tumor therapy for rectal cancer, including radiotherapy, chemotherapy, immune checkpoint inhibitors, or surgery.

7. Adequate organ function (without blood product or growth factor support during screening):

   ANC ≥1.5×10⁹/L; platelets ≥100×10⁹/L; hemoglobin ≥8.5 g/dL.

   TSH ≤1×ULN (if abnormal, T3/T4 must be within normal limits for enrollment).

   Bilirubin ≤1.5×ULN; ALT and AST ≤2.5×ULN.

   Serum creatinine ≤1.5×ULN or CrCl ≥50 mL/min (Cockcroft-Gault formula).

   INR ≤1.5×ULN; APTT ≤1.5×ULN.

8. Negative pregnancy test (β-hCG) for women of childbearing potential before treatment initiation.Women of childbearing potential and men (who are sexually active with women of childbearing potential) must agree to use effective contraception continuously during treatment and for 6 months after the last dose.
9. Voluntary participation with written informed consent.

Exclusion Criteria:

1. History of other malignancies within the past 5 years, except adequately treated cervical carcinoma in situ, cutaneous squamous cell carcinoma, or basal cell carcinoma.
2. Major surgery or severe trauma within 4 weeks prior to first study drug administration.
3. Systemic corticosteroids (equivalent to prednisone >10 mg/day) or other immunosuppressive therapy within 2 weeks prior to study drug administration.
4. Active, known, or suspected autoimmune disease. Patients with stable conditions not requiring systemic immunosuppression (e.g., type 1 diabetes, hypothyroidism on hormone replacement, or skin disorders without systemic treatment) are eligible.
5. Immunodeficiency, including HIV positivity, other acquired/congenital immune deficiencies, or history of organ or allogeneic bone marrow transplantation.
6. Congestive heart failure, uncontrolled arrhythmia, myocardial infarction within 6 months, unstable angina, stroke, or other conditions precluding surgery.
7. Pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severely impaired pulmonary function.
8. Uncontrolled symptomatic brain metastases, poorly controlled psychiatric disorders, or severe intellectual/cognitive impairment.
9. Known substance abuse or drug addiction.
10. Clinically significant bleeding symptoms or clear bleeding tendency within 3 months prior to enrollment.
11. Severe active infection requiring IV antibiotics during screening.
12. Known hypersensitivity to Retlirafusp alfa or any excipients (polysorbate 80 (II), sucrose, citric acid, sodium citrate, water for injection, etc.), or severe allergic reactions to other monoclonal antibodies.
13. Active hepatitis B (HBV DNA >2000 IU/mL or 10⁴ copies/mL), or hepatitis C antibody-positive with HCV RNA above the lower limit of detection.
14. Receipt or planned receipt of live vaccine within 30 days prior to immunotherapy administration.
15. Intolerance to chemotherapy.
16. Inability to comply with the protocol or follow-up.
17. Other conditions deemed unsuitable for participation 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: Short-course radiotherapy combined with Retlirafusp alfa and CAPOX chemotherapy

Drug: Short-course radiotherapy combined with Retlirafusp alfa and CAPOX chemotherapy; Short-course radiotherapy + Retlirafusp alfa + CAPOX chemotherapy for 1 cycle, followed by Retlirafusp alfa + CAPOX chemotherapy for 3 cycles. Cycle 1: Retlirafusp alfa: 1800 mg or 30 mg/kg, IV infusion over 30-60 min, D1, q3w; administered at least 30 min before chemotherapy. Oxaliplatin: 130 mg/m², IV infusion over ≥2 h, D1, q3w. Capecitabine: 1000 mg/m², PO, twice daily (total 2000 mg/m²/day) for 14 days, q3w. Short-course radiotherapy: 25 Gy in 5 fractions, D2-D6. Cycles 2-4: Retlirafusp alfa: 1800 mg or 30 mg/kg, IV infusion over 30-60 min, D1, q3w. Oxaliplatin: 130 mg/m², IV infusion over ≥2 h, D1, q3w. Capecitabine: 1000 mg/m², PO, twice daily (total 2000 mg/m²/day) for 14 days, q3w. Efficacy evaluation is performed after cycles 2 and 4. Patients are reassessed 2-4 weeks after the last treatment. Those achieving clinical complete response (cCR) may opt for watch-and-wait (W&W). Non-cCR patients (near-CR, PR, or SD) are recommended to undergo total mesorectal excision (

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response Rate (cCR+pCR)	Proportion of patients achieving clinical complete response (cCR, no tumor residue by imaging and endoscopy) after neoadjuvant therapy or pathological complete response (pCR, no residual viable tumor cells in tumor bed) post-surgery, reflecting overall tumor eradication.	cCR assessed 2-4 weeks post-neoadjuvant therapy; pCR assessed within 2 weeks post-surgery; follow-up up to ~6 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Proportion of patients achieving complete response (CR) or partial response (PR) per RECIST 1.1 criteria on imaging.	Imaging assessment after cycles 2 and 4, and post-surgery; follow-up up to ~6 months.
Pathological Complete Response (pCR)	Proportion of patients with no residual viable tumor cells in the tumor bed (ypT0N0) after neoadjuvant therapy and surgery.	Pathological assessment within 2 weeks post-surgery; follow-up up to ~6 months.
Major Pathological Response (MPR)	Proportion of patients with ≤10% residual viable tumor cells in the tumor bed post-surgery.	Pathological assessment within 2 weeks post-surgery; follow-up up to ~6 months.
TRG Grade	Assessment of pathological tumor regression grade (TRG 0-3) per AJCC 8th edition.	Pathological assessment within 2 weeks post-surgery; follow-up up to ~6 months.
Event-Free Survival (EFS)	Time from treatment initiation to first occurrence of: disease progression (local/distant) during neoadjuvant therapy, treatment discontinuation (toxicity/patient withdrawal), local/distant recurrence, new primary tumor, or death from any cause.	From treatment initiation to first event, follow-up every 3 months, up to 36 months.
Overall Survival (OS)	Time from first dose to death from any cause (censored at last follow-up for alive or lost patients).	From first dose to death or last follow-up, follow-up every 3 months, up to 36 months.
Adverse Event Rate	Incidence and severity of adverse events per NCI CTCAE 6.0; surgical complications graded per Clavien-Dindo classification.	Continuous monitoring from informed consent to 90 days post-last dose; follow-up up to ~36 months.
Quality of Life (EORTC QLQ-CR29)	Assessment of bowel symptoms, sexual function, and overall quality of life; higher scores indicate worse symptoms or better function.	Assessed at baseline, pre-surgery post-neoadjuvant therapy, and 3, 6, 12 months post-surgery; follow-up up to 12 months.
Anal Function (LARS Score)	Assessment of low anterior resection syndrome, total score 0-42 (0-20: no/mild LARS; 21-29: moderate; 30-42: severe).	Assessed at baseline, pre-surgery post-neoadjuvant therapy, and 3, 6, 12 months post-surgery; follow-up up to 12 months.
Emotional Changes (GAD-7)	Assessment of anxiety status during treatment, total score 0-21; ≥10 indicates moderate-to-severe anxiety.	Generalized Anxiety Disorder Scale (GAD-7) assessed with a maximum follow-up of 12 months.
Biomarker Exploration	Collection of tumor tissue and peripheral blood samples for genomic, transcriptomic, proteomic, and immune microenvironment analyses to identify potential predictive and prognostic biomarkers associated with efficacy and safety.	Tumor tissue and peripheral blood collected at baseline; peripheral blood collected periodically during treatment; follow-up up to ~6 months.

Collaborators and Investigators

• Sponsor: Harbin Medical University

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2026
• Primary Completion (Estimated): May 27, 2028
• Study Completion (Estimated): May 27, 2029

Study Registration Dates

• First Submitted: June 17, 2026
• First Submitted That Met QC Criteria: June 17, 2026
• First Posted (Actual): June 23, 2026

Study Record Updates

• Last Update Posted (Actual): June 23, 2026
• Last Update Submitted That Met QC Criteria: June 17, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: neoadjuvant therapy; locally advanced rectal cancer; Retlirafusp alfa
• Other Study ID Numbers: SHR-1701-HLJ-001

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