Short-Course Radiotherapy Combined with Intracavitary Brachytherapy Followed by Pucotenlimab, Bevacizumab, Oxaliplatin, and Trifluridine/Tipiracil (TAS-102) for Total Neoadjuvant Therapy of Microsatellite Stable (MSS) Locally Advanced Low Rectal Cancer

Phase 2

Not yet recruiting

• Conditions: Rectal Adenocarcinoma
• Interventions: Drug: Pucotenlimab; Drug: Bevacizumab; Drug: Oxaliplatin; Drug: Trifluridine/Tipiracil Hydrochloride; Radiation: Short-course radiotherapy; Radiation: intracavitary brachytherapy

• Registration Number: NCT06872606
• Lead Sponsor: Sir Run Run Shaw Hospital

Brief Summary

A Prospective Single-Arm Study of Short-Course Radiotherapy Followed by PD-1 Monoclonal Antibody, Bevacizumab, Oxaliplatin, and Trifluridine/Tipiracil for Total Neoadjuvant Therapy in MSS Locally Advanced Low Rectal Cancer. This is a Non-Randomized, Single Group Assignment, Open Label, Phase: Phase II study. The Primary Objective is to assess the organ preservation rate (clinical complete response, cCR) after total neoadjuvant therapy. Secondary Objectives are Tumor regression grade (TRG), 3-year overall survival (OS) and disease-free survival (DFS), and Safety and quality of life (QoL). In this study, the investigators will perform the multi-dimensional omics study to explore the tumors microenvironments, explore the characteristics of the treatment benefit population, and try to construct an efficacy prediction model to screen the treatment benefit population early and implement precise treatment.

Detailed Description

Not available

Study Timeline

• Status Verified: 2025-03
• Study First Submitted: 2025-03-05
• Study First Submitted QC: 2025-03-10
• Last Update Submitted: 2025-03-10
• Study First Posted: 2025-03-12
• Last Update Posted: 2025-03-12
• Study Start: 2025-04-01
• Primary Completion: 2026-04-01
• Study Completion: 2028-04-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 33

Inclusion Criteria

1. Patients who are willing to receive neoadjuvant therapy.
2. ≧18 years old.
3. Diagnosed by digital rectal examination, colonoscopy, and high-resolution MRI of the pelvis, the tumor is less than or equal to 5 cm from the anus.
4. Histologically diagnosed as rectal adenocarcinoma.
5. Clinical stage: cT2-4a N+ or cT3/T4a N0 (MRI/CT-confirmed).
6. MSS/pMMR status confirmed by immunohistochemistry or PCR before treatment .
7. ECOG Scale of Performance Status score 0-1 point.
8. Adequate organ function (hematologic, hepatic, renal).
9. Have not received anti-tumor and immunotherapy before enrollment.
10. Laboratory inspections must meet the following standards:

1. White blood cell count>3.5×109/L, absolute value of neutrophils>1.8×109/L, platelet count ≥75×109/L, hemoglobin ≥100g/L; 2) INR≤1.5, and APTT≤1.5 times the upper limit of normal or partial prothrombin time (PT) ≤1.5 times the upper limit of normal; 3) Total bilirubin ≤ 1.25 times the upper limit of normal; ALT and AST < 5 times the upper limit of normal; 4) 24h creatinine clearance >50mL/min or serum creatinine <1.5 times the upper limit of normal.

11. Voluntarily participate in this study and sign the informed consent.

Exclusion Criteria

1. History of other malignant diseases in the past 5 years.
2. Patients with metastases from other sites (stage IV patients).
3. Patients withT4b or positive lateral lymph nodes by pelvic contrast-enhanced CT and pelvic high-resolution MRI.
4. Patients with intestinal obstruction, intestinal perforation, intestinal bleeding, etc. requiring emergency surgery.
5. Known allergic to oxaliplatin, PD-1 monoclonal antibody and other intervention drugs.
6. Pathologically suggested signet ring cell carcinoma and mucinous adenocarcinoma.
7. dMMR or MSI-H patients.
8. The patient is accompanied by any unstable systemic disease, including but not limited to: severe infection, uncontrolled diabetes, hypertension uncontrolled by medication, unstable angina, cerebrovascular accident or transient cerebral ischemia, myocardial Infarction, congestive heart failure, severe cardiac arrhythmia requiring medication, hepatic, renal or metabolic disease; disease affecting the patient's life.
9. The disease (such as mental illness, etc.) or condition (such as alcoholism or drug abuse, etc.) associated with the patient will increase the risk of the patient receiving the trial drug treatment or affect the patient's compliance with the trial requirements, or may confuse the research results.
10. Active autoimmune disease that may worsen while receiving immunostimulants.
11. Known history of positive HIV test or known acquired immunodeficiency syndrome.
12. Patients who are using immunosuppressive agents, except for the following conditions:

1. Intranasal, inhaled, topical steroids, or topical steroid injections (eg, intra-articular injections); 2) Physiological doses of systemic corticosteroids ≤10 mg/day prednisone or equivalent; 3) Steroids used to prevent allergic reactions (eg, before CT scan). 13. Received any other experimental drug treatment or participated in another interventional clinical trial within 30 days before screening 14. Women who are pregnant or breastfeeding or who plan to become pregnant or breastfeeding during the study period; men or women who are unwilling to take effective contraceptive measures.

15. Vulnerable groups, including mentally ill, cognitively impaired, critically ill patients, minors, etc.

16. Other conditions that the investigator judges that the patient is not suitable to participate in the clinical study, etc.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
POBTAS Trial Arm	Pucotenlimab	Intervention: 1.Radiotherapy: 1. Phase 1 (Short-Course External Radiotherapy): Intensity-modulated radiotherapy (IMRT) at 5 Gy X 5F, completed within 1 week. 2. Phase 2 (Intracavitary Brachytherapy): Administered during weeks 5-6, targeting residual lesions with 3Gy X 3F, completed within 1 week. 2.Systemic Therapy Post-Initial Radiotherapy: 1. Cycles 1-2: PD-1 antibody immunotherapy (pucotenlimab) combined with bevacizumab, oxaliplatin, and trifluridine/tipiracil (TAS-102). 2. Cycles 3-4: Sequential PD-1 immunotherapy + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 4). 3.Post-Cycle 4 Evaluation: If ypT0 (local pathological complete response): Enter follow-up observation. If non-CR: Proceed to Step 4. 4.Extended Systemic Therapy for Non-CR Patients: Cycles 5-8: Repeat PD-1 immunotherapy + bevacizumab + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 8). 5.Post-Cycle 8 Evaluation: If ypT0: Enter follow-up observation. If non-ypT0: Proceed to TME surgery.
POBTAS Trial Arm	Bevacizumab	Intervention: 1.Radiotherapy: 1. Phase 1 (Short-Course External Radiotherapy): Intensity-modulated radiotherapy (IMRT) at 5 Gy X 5F, completed within 1 week. 2. Phase 2 (Intracavitary Brachytherapy): Administered during weeks 5-6, targeting residual lesions with 3Gy X 3F, completed within 1 week. 2.Systemic Therapy Post-Initial Radiotherapy: 1. Cycles 1-2: PD-1 antibody immunotherapy (pucotenlimab) combined with bevacizumab, oxaliplatin, and trifluridine/tipiracil (TAS-102). 2. Cycles 3-4: Sequential PD-1 immunotherapy + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 4). 3.Post-Cycle 4 Evaluation: If ypT0 (local pathological complete response): Enter follow-up observation. If non-CR: Proceed to Step 4. 4.Extended Systemic Therapy for Non-CR Patients: Cycles 5-8: Repeat PD-1 immunotherapy + bevacizumab + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 8). 5.Post-Cycle 8 Evaluation: If ypT0: Enter follow-up observation. If non-ypT0: Proceed to TME surgery.
POBTAS Trial Arm	Oxaliplatin	Intervention: 1.Radiotherapy: 1. Phase 1 (Short-Course External Radiotherapy): Intensity-modulated radiotherapy (IMRT) at 5 Gy X 5F, completed within 1 week. 2. Phase 2 (Intracavitary Brachytherapy): Administered during weeks 5-6, targeting residual lesions with 3Gy X 3F, completed within 1 week. 2.Systemic Therapy Post-Initial Radiotherapy: 1. Cycles 1-2: PD-1 antibody immunotherapy (pucotenlimab) combined with bevacizumab, oxaliplatin, and trifluridine/tipiracil (TAS-102). 2. Cycles 3-4: Sequential PD-1 immunotherapy + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 4). 3.Post-Cycle 4 Evaluation: If ypT0 (local pathological complete response): Enter follow-up observation. If non-CR: Proceed to Step 4. 4.Extended Systemic Therapy for Non-CR Patients: Cycles 5-8: Repeat PD-1 immunotherapy + bevacizumab + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 8). 5.Post-Cycle 8 Evaluation: If ypT0: Enter follow-up observation. If non-ypT0: Proceed to TME surgery.
POBTAS Trial Arm	Trifluridine/Tipiracil Hydrochloride	Intervention: 1.Radiotherapy: 1. Phase 1 (Short-Course External Radiotherapy): Intensity-modulated radiotherapy (IMRT) at 5 Gy X 5F, completed within 1 week. 2. Phase 2 (Intracavitary Brachytherapy): Administered during weeks 5-6, targeting residual lesions with 3Gy X 3F, completed within 1 week. 2.Systemic Therapy Post-Initial Radiotherapy: 1. Cycles 1-2: PD-1 antibody immunotherapy (pucotenlimab) combined with bevacizumab, oxaliplatin, and trifluridine/tipiracil (TAS-102). 2. Cycles 3-4: Sequential PD-1 immunotherapy + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 4). 3.Post-Cycle 4 Evaluation: If ypT0 (local pathological complete response): Enter follow-up observation. If non-CR: Proceed to Step 4. 4.Extended Systemic Therapy for Non-CR Patients: Cycles 5-8: Repeat PD-1 immunotherapy + bevacizumab + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 8). 5.Post-Cycle 8 Evaluation: If ypT0: Enter follow-up observation. If non-ypT0: Proceed to TME surgery.
POBTAS Trial Arm	Short-course radiotherapy	Intervention: 1.Radiotherapy: 1. Phase 1 (Short-Course External Radiotherapy): Intensity-modulated radiotherapy (IMRT) at 5 Gy X 5F, completed within 1 week. 2. Phase 2 (Intracavitary Brachytherapy): Administered during weeks 5-6, targeting residual lesions with 3Gy X 3F, completed within 1 week. 2.Systemic Therapy Post-Initial Radiotherapy: 1. Cycles 1-2: PD-1 antibody immunotherapy (pucotenlimab) combined with bevacizumab, oxaliplatin, and trifluridine/tipiracil (TAS-102). 2. Cycles 3-4: Sequential PD-1 immunotherapy + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 4). 3.Post-Cycle 4 Evaluation: If ypT0 (local pathological complete response): Enter follow-up observation. If non-CR: Proceed to Step 4. 4.Extended Systemic Therapy for Non-CR Patients: Cycles 5-8: Repeat PD-1 immunotherapy + bevacizumab + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 8). 5.Post-Cycle 8 Evaluation: If ypT0: Enter follow-up observation. If non-ypT0: Proceed to TME surgery.
POBTAS Trial Arm	intracavitary brachytherapy	Intervention: 1.Radiotherapy: 1. Phase 1 (Short-Course External Radiotherapy): Intensity-modulated radiotherapy (IMRT) at 5 Gy X 5F, completed within 1 week. 2. Phase 2 (Intracavitary Brachytherapy): Administered during weeks 5-6, targeting residual lesions with 3Gy X 3F, completed within 1 week. 2.Systemic Therapy Post-Initial Radiotherapy: 1. Cycles 1-2: PD-1 antibody immunotherapy (pucotenlimab) combined with bevacizumab, oxaliplatin, and trifluridine/tipiracil (TAS-102). 2. Cycles 3-4: Sequential PD-1 immunotherapy + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 4). 3.Post-Cycle 4 Evaluation: If ypT0 (local pathological complete response): Enter follow-up observation. If non-CR: Proceed to Step 4. 4.Extended Systemic Therapy for Non-CR Patients: Cycles 5-8: Repeat PD-1 immunotherapy + bevacizumab + oxaliplatin + TAS-102 (bevacizumab omitted in Cycle 8). 5.Post-Cycle 8 Evaluation: If ypT0: Enter follow-up observation. If non-ypT0: Proceed to TME surgery.

Primary Outcome Measures

Name	Time	Method
Organ preservation rate	Up to 2 weeks (once evaluation or biopsy is done)	The organ preservation rate was calculated as the percentage of participants who achieved cCR and were spared from total mesorectal excision (TME) surgery relative to the total study cohort. Clinical complete response (cCR) requires both histopathological confirmation (no viable tumor cells in biopsy specimens) and radiographic confirmation (absence of tumor on CT, MRI, or PET-CT).

Secondary Outcome Measures

Name	Time	Method
Total mesorectal excision rate after recurrence	Through study completion, an average of 3 year	Population who recurrent and have Salvage total mesorectal excision after achieving complete clinical response after total neoadjuvant therapy
Tumor regression grade	After 2 weeks (once biopsy or local excision is done)	Tumor Regression Grade（TRG）will be done via pathologic assessment on the surgical specimen with AJCC/CAP TRG system
Overall survival	Up to 3 years	The proportion of participants who remain survival at 3 years
Progression free survival	Up to 3 years	The proportion of participants who remain progression free at 3 years
TRAEs	Up to 3 years	Number of participants with treatment-related adverse events as assessed by NCI-CTCAE v5.0
Surgical Complications	Up to 3 years	Surgical Complications of biopsy, local excision or total mesorectal resection procedure for patients as assessed by Clavien-Dindo classification.
QoL	Up to 3 years	Quality of life of the patients in total neoadjuvant settings as assessed by Functional Assessment of Cancer Therapy - Colorectal (FACT-C) questionnaire liscenced from The Functional Assessment of Chronic Illness Therapy System ("FACIT System"). By using the Manual scoring template, some items are reverse scored. Subscale scores, total scores and TOI scores. The higher the score, the better the QOL.
Total mesorectal excision rate	After 2 weeks (once biopsy or local excision is done)	Population who not achieve complete clinical response and have TME surgery after total neoadjuvant therapy

Trial Locations

Locations (1)

Sir Run Run Shaw Hospital, Zhejiang University School of Medicine; 🇨🇳 Hangzhou, Zhejiang, China