Low-Dose Radiotherapy to Sensitize Pucotenlimab Plus CAPEOX for pMMR Locally Advanced Rectal Cancer

May 1, 2026 updated by: Pei-Rong Ding, Sun Yat-sen University

A Randomized, Two-Arm, Open-Label Phase II Trial of Low-Dose Radiotherapy Sensitization Combined With Pucotenlimab and CAPEOX as Neoadjuvant Therapy for pMMR/MSS Locally Advanced Rectal Adenocarcinoma

This is a prospective, open-label, randomized, parallel-group phase II trial evaluating the efficacy and safety of a low-dose radiotherapy sensitization strategy combined with a PD-1 antibody (pucotenlimab) and CAPEOX as neoadjuvant therapy in patients with pMMR/MSS locally advanced rectal adenocarcinoma. Participants will be randomized 1:1 to receive either 2 Gy or 5 Gy low-dose radiotherapy. Low-dose radiotherapy is delivered as a single fraction of 2 Gy (Arm A) or 5 Gy (Arm B). On the day after radiotherapy, participants will start pucotenlimab 200 mg IV Q3W (administered on Day 2 of each 21-day cycle) plus CAPEOX chemotherapy. Early response will be assessed after 2 cycles using endoscopy and pelvic MRI to guide subsequent treatment: participants with partial response may discontinue radiotherapy and continue neoadjuvant systemic therapy; participants with stable disease may switch to standard chemoradiotherapy; participants with progressive disease will receive multidisciplinary-team-guided salvage therapy. After 4 cycles, participants with clinical complete response may adopt a watch-and-wait strategy; otherwise, they will undergo radical surgery 2-4 weeks after completion of neoadjuvant therapy. Long-term follow-up will include recurrence and survival outcomes and quality of life.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Rectal cancer remains a major global health burden, with a higher risk of local recurrence and worse prognosis compared with colon cancer. The introduction of total mesorectal excision (TME) has substantially reduced local recurrence rates, and the incorporation of peri-operative radiotherapy and chemotherapy has further improved oncologic outcomes. Current National Comprehensive Cancer Network (NCCN) guidelines recommend pre-operative chemoradiotherapy followed by radical surgery for patients with stage II-III locally advanced rectal cancer.In recent years, total neoadjuvant therapy (TNT) has emerged as an optimized treatment paradigm, increasing pathologic complete response (pCR) rates to approximately 20-40%, and even higher when combined with immunotherapy. For patients achieving a clinical complete response (cCR) after neoadjuvant therapy, a non-operative "watch-and-wait" strategy has been shown to be safe and effective, allowing organ preservation without compromising long-term oncologic outcomes.However, most patients with proficient mismatch repair (pMMR) or microsatellite-stable (MSS) rectal cancer derive limited benefit from immune checkpoint blockade alone. Preclinical and clinical evidence suggests that radiotherapy, particularly low-dose radiotherapy (LDRT), may enhance antitumor immune responses by modulating the tumor microenvironment and promoting immune sensitization. Whether different low-dose radiotherapy regimens can differentially enhance the efficacy of immunotherapy combined with chemotherapy in pMMR/MSS locally advanced rectal cancer remains unknown.To address this question, the present study is designed as a prospective, open-label, randomized, parallel-group phase II clinical trial evaluating a low-dose radiotherapy sensitization strategy combined with a PD-1 antibody (pucotenlimab) and CAPEOX chemotherapy as neoadjuvant treatment.Eligible participants with pMMR/MSS locally advanced rectal adenocarcinoma will be randomized in a 1:1 ratio to receive either 2 Gy or 5 Gy low-dose radiotherapy. On the day following radiotherapy, all participants will initiate systemic treatment with pucotenlimab 200 mg administered intravenously every 3 weeks (Q3W) on Day 2, in combination with CAPEOX chemotherapy in 21-day cycles.Treatment response will be assessed early after 2 cycles of neoadjuvant therapy using endoscopy and pelvic magnetic resonance imaging (MRI). Based on response evaluation, subsequent treatment will be adapted: participants demonstrating partial response may discontinue radiotherapy and continue systemic neoadjuvant therapy; those with stable disease may transition to standard chemoradiotherapy; and those with progressive disease will receive multidisciplinary team-guided salvage treatment.After completion of 4 cycles of neoadjuvant therapy, response will be reassessed. Participants achieving a clinical complete response may adopt a watch-and-wait strategy with close surveillance, whereas those without cCR will proceed to radical surgery, typically performed 2-4 weeks after completion of neoadjuvant treatment.The primary objective of this study is to compare the complete response rate, defined as the sum of clinical complete response and pathological complete response, between the two low-dose radiotherapy regimens. Secondary objectives include long-term disease control, survival outcomes, surgical quality metrics, postoperative morbidity, stoma rates, and patient-reported quality of life. This study aims to determine whether optimization of low-dose radiotherapy can enhance immune-chemotherapy efficacy and increase organ preservation opportunities in patients with pMMR/MSS locally advanced rectal cancer.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
50

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • China
    • Guanggong
      • Guangzhou, Guanggong, China, 510060
        • Recruiting
        • Dept. of Colorectal Surgery, Sun Yat-sen University Cancer Center. Yuexiu District, Dongfeng East Road 651
        • Principal Investigator:
          • Pei-Rong Ding
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria

  • Written informed consent provided prior to any study-specific procedures.
  • Age 18 to 75 years at the time of enrollment.
  • Histologically confirmed rectal adenocarcinoma.
  • Tumor located within 10 cm from the anal verge, as assessed by endoscopy or imaging.
  • Locally advanced disease, defined as clinical stage T2N+ or T3-T4a (any N) based on pelvic magnetic resonance imaging (MRI).
  • Proficient mismatch repair (pMMR) or microsatellite-stable (MSS) tumor status confirmed by immunohistochemistry or molecular testing.
  • No evidence of distant metastasis on preoperative imaging, including chest, abdominal, and pelvic computed tomography (CT).
  • Circumferential resection margin (CRM) ≥2 mm and no involvement of the mesorectal fascia on baseline MRI.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
  • Adequate organ function as defined by:
  • Absolute neutrophil count ≥1.5 × 10⁹/L
  • Platelet count ≥100 × 10⁹/L
  • Hemoglobin ≥90 g/L
  • Total bilirubin ≤1.5 × upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN
  • Creatinine clearance ≥50 mL/min
  • Thyroid-stimulating hormone (TSH) within normal limits
  • Women of childbearing potential must have a negative pregnancy test and agree to use effective contraception during the study and for a protocol-defined period after the last dose.
  • Men with partners of childbearing potential must agree to use effective contraception during the study and for a protocol-defined period after the last dose.

Exclusion Criteria

  • Clinical T4b disease, defined as tumor invasion into adjacent organs or structures on baseline imaging.
  • Circumferential resection margin (CRM) <2 mm or definite involvement of the mesorectal fascia on baseline MRI.
  • Evidence of distant metastasis outside the pelvis.
  • Prior pelvic or abdominal radiotherapy.
  • Prior treatment with immune checkpoint inhibitors or other systemic anticancer therapy for rectal cancer.
  • Active or history of autoimmune disease requiring systemic treatment, except for conditions considered low risk for recurrence (e.g., vitiligo, resolved childhood asthma).
  • Ongoing use of systemic immunosuppressive therapy, including corticosteroids equivalent to >10 mg/day of prednisone, within 2 weeks prior to enrollment.
  • Known human immunodeficiency virus (HIV) infection.
  • Active hepatitis B virus infection with positive hepatitis B surface antigen and high viral load, or hepatitis C virus infection requiring treatment.
  • Uncontrolled active infection or other serious medical condition that, in the investigator's judgment, would compromise patient safety or study compliance.
  • History of another malignancy within 5 years, except for adequately treated basal cell carcinoma of the skin, cervical carcinoma in situ, or other malignancies with negligible risk of recurrence.
  • Known hypersensitivity or allergy to pucotenlimab, oxaliplatin, capecitabine, or any of their excipients.
  • Pregnant or breastfeeding women.
  • Any condition that, in the investigator's opinion, makes the participant unsuitable for study participation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: 2 Gy LDRT + Pucotenlimab + CAPEOX
Neoadjuvant low-dose radiotherapy (2 Gy) followed by pucotenlimab 200 mg IV Q3W plus CAPEOX chemotherapy.
Radiation: Low-dose radiotherapy
Low-dose radiotherapy delivered by linear accelerator to the primary rectal tumor and regional lymphatic drainage areas using IMRT or 3D-CRT techniques. Participants receive either 2 Gy or 5 Gy according to randomized assignment, administered prior to initiation of systemic neoadjuvant therapy.
Drug: Pucotenlimab
Pucotenlimab is a programmed cell death protein 1 (PD-1) monoclonal antibody. It is administered at a fixed dose of 200 mg by intravenous infusion on Day 2 of each 21-day cycle, every 3 weeks (Q3W), during the neoadjuvant treatment phase.
Drug: CAPEOX/XELOX
CAPEOX chemotherapy consists of oxaliplatin 130 mg/m² administered intravenously on Day 1 and capecitabine 1000-1250 mg/m² administered orally twice daily on Days 1-14 of each 21-day cycle during neoadjuvant therapy.
Experimental: 5 Gy LDRT + Pucotenlimab + CAPEOX
Neoadjuvant low-dose radiotherapy (5 Gy) followed by pucotenlimab 200 mg IV Q3W plus CAPEOX chemotherapy.
Radiation: Low-dose radiotherapy
Low-dose radiotherapy delivered by linear accelerator to the primary rectal tumor and regional lymphatic drainage areas using IMRT or 3D-CRT techniques. Participants receive either 2 Gy or 5 Gy according to randomized assignment, administered prior to initiation of systemic neoadjuvant therapy.
Drug: Pucotenlimab
Pucotenlimab is a programmed cell death protein 1 (PD-1) monoclonal antibody. It is administered at a fixed dose of 200 mg by intravenous infusion on Day 2 of each 21-day cycle, every 3 weeks (Q3W), during the neoadjuvant treatment phase.
Drug: CAPEOX/XELOX
CAPEOX chemotherapy consists of oxaliplatin 130 mg/m² administered intravenously on Day 1 and capecitabine 1000-1250 mg/m² administered orally twice daily on Days 1-14 of each 21-day cycle during neoadjuvant therapy.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Complete Response Rate (CR)
Time Frame: From the start of neoadjuvant therapy until the completion of pre-operative assessment (approximately 12 weeks) and the time of surgery (approximately 14-16 weeks).
The Combined CR rate is defined as the percentage of participants achieving either Clinical Complete Response (cCR) or Pathologic Complete Response (pCR). cCR is assessed via pelvic MRI, digital rectal examination (DRE), and endoscopy following the completion of 4 cycles of neoadjuvant therapy (each cycle is 21 days). For patients who do not achieve cCR and subsequently undergo radical surgery (scheduled 2-4 weeks after the last dose of neoadjuvant therapy), pCR is assessed by pathological examination of the resected surgical specimen (Tumor Regression Grading, TRG 0) according to the AJCC/College of American Pathologists (CAP) guidelines.
From the start of neoadjuvant therapy until the completion of pre-operative assessment (approximately 12 weeks) and the time of surgery (approximately 14-16 weeks).

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
3-year Disease-Free Survival (DFS)
Time Frame: Up to 3 years after randomization.
Disease-free survival is defined as the time from randomization to the first documented occurrence of tumor recurrence (local or distant) or death from any cause, whichever occurs first.
Up to 3 years after randomization.
5-year Overall Survival (OS)
Time Frame: Up to 5 years after randomization.
Overall survival is defined as the time from randomization to death from any cause.
Up to 5 years after randomization.
Distant Metastasis Rate
Time Frame: Up to 5 years after randomization.
The proportion of participants who develop distant metastasis during follow-up, confirmed by radiologic or pathologic assessment.
Up to 5 years after randomization.
R0 Resection Rate
Time Frame: At the time of surgery.
The proportion of participants who achieve microscopically margin-negative (R0) resection at the time of surgery.
At the time of surgery.
Postoperative Surgical Complication Rate
Time Frame: Within 30 days after surgery.
The proportion of participants experiencing postoperative surgical complications, graded according to standard surgical complication criteria.
Within 30 days after surgery.
Protective Stoma Rate
Time Frame: At the time of surgery.
The proportion of participants who undergo prophylactic diverting stoma creation at the time of surgery.
At the time of surgery.
Quality of Life (EORTC QLQ-C30)
Time Frame: From baseline through follow-up (up to 5 years).
Quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), version 3.0.
From baseline through follow-up (up to 5 years).

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Sun Yat-sen University

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Pei-Rong Ding, Sun Yat-sen University Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 15, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2027

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 1, 2032

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 9, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 3, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 4, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 7, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 1, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2025-FXY-301
  • B2025-700 (Sun Yat-sen University Cancer Center)

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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