Short-Course Radiotherapy Followed by CAPOX With or Without Iparomlimab and Tuvonralimab in pMMR/MSS Locally Advanced Rectal Cancer

Phase 3RecruitingNCT07686640

Shandong Cancer Hospital and Institute180 enrolled

Overview

This multicenter, randomized, controlled, phase III trial evaluates whether adding iparomlimab and tuvonralimab injection to CAPOX consolidation chemotherapy after short-course radiotherapy improves tumor response in patients with treatment-naive, proficient mismatch repair/microsatellite-stable (pMMR/MSS) locally advanced rectal adenocarcinoma. Eligible patients will be randomly assigned in a 1:1 ratio to receive short-course radiotherapy followed by CAPOX plus iparomlimab and tuvonralimab, or short-course radiotherapy followed by CAPOX alone. After total neoadjuvant therapy, patients with a clinical complete response may undergo a Watch-and-Wait strategy, whereas other patients will undergo total mesorectal excision according to standard clinical practice. The primary endpoint is complete response rate, defined as pathologic complete response after surgery or clinical complete response sustained for more than 1 year. Secondary endpoints include 3-year relapse-free survival, 3-year overall survival, sphincter preservation rate, and grade 3-4 acute adverse events. Exploratory analyses will assess tissue and blood biomarkers associated with treatment response.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

180

Conditions

Local Advanced Rectal Cancer Radiotherapy

Interventions

Short-Course RadiotherapyRADIATION

Short-course external-beam radiotherapy will be delivered to the rectal primary tumor and corresponding lymphatic drainage regions using IMRT or VMAT. The prescribed dose is 25 Gy in 5 fractions over 1 week. No concurrent chemotherapy will be administered during short-course radiotherapy.

Consolidation treatment (With ICIs)DRUG

Iparomlimab and tuvonralimab injection will be administered at 5 mg/kg by intravenous infusion every 21 days for 6 cycles. CAPOX chemotherapy will consist of oxaliplatin 130 mg/m² intravenously on day 1 plus capecitabine 1000 mg/m² orally twice daily on days 1-14 of each 21-day cycle, for 6 cycles.

Consolidation treatment (Without ICIs)DRUG

CAPOX chemotherapy will consist of oxaliplatin 130 mg/m² intravenously on day 1 plus capecitabine 1000 mg/m² orally twice daily on days 1-14 of each 21-day cycle, for 6 cycles.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients aged 18-75 years with histologically confirmed pMMR/MSS rectal adenocarcinoma are eligible if they have MRI-defined clinical stage II or III disease according to AJCC 8th edition, tumor located within 12 cm from the anal verge, and at least one high-risk feature, including cT4b, cN2, EMVI positivity, MRF positivity, lateral lymph node positivity, tumor deposits, or tumor located ≤5 cm from the anal verge. Patients must have no distant metastasis, ECOG performance status 0-1, life expectancy greater than 6 months, and adequate hematologic, hepatic, and renal function Exclusion Criteria: * active or prior autoimmune disease requiring systemic treatment, use of immunosuppressive therapy or systemic corticosteroids at immunosuppressive doses, severe hypersensitivity to monoclonal antibodies, uncontrolled cardiac disease, significant coagulopathy or bleeding tendency, active infection, interstitial lung disease or severe pulmonary dysfunction, HIV infection or active hepatitis, prior or concurrent malignancy except specified cured cancers, recent investigational drug use, planned use of other systemic antitumor therapy during the study, pregnancy or breastfeeding, and any other condition judged by the investigator to make participation unsuitable.

Outcomes

Primary Outcomes

Complete Response (CR) Rate

Complete response rate is defined as the proportion of patients who achieve either pathologic complete response (pCR) after surgery or sustained clinical complete response (cCR) for more than 1 year during Watch-and-Wait follow-up.

Time frame: From randomization to completion of definitive response assessment, including surgical pathological assessment after total neoadjuvant therapy or confirmation of sustained clinical complete response after at least 12 months of Watch-and-Wait follow-up

Secondary Outcomes

3-Year Relapse-Free Survival (RFS)

Relapse-free survival is defined as the time from randomization to the first evidence of disease relapse or recurrence. Patients without relapse/recurrence or death will be censored at the date of last disease assessment.

Time frame: From randomization to the first documented disease relapse/recurrence, death from any cause, or 3 years after randomization, whichever occurs first.

3-Year Overall Survival (OS)

Overall survival is defined as the time from randomization to death from any cause. Patients who are alive at the time of analysis will be censored at the date of last known survival follow-up.

Time frame: From randomization to death from any cause or 3 years after randomization, whichever occurs first.

Sphincter Preservation Rate

Sphincter preservation rate is defined as the proportion of patients who successfully preserve anal sphincter structure and function and avoid permanent colostomy.

Time frame: From randomization to completion of definitive surgery, or to at least 12 months after initiation of Watch-and-Wait follow-up for patients who do not undergo surgery; approximately up to 18-24 months after randomization.

Incidence of Grade 3-4 Acute Adverse Events

Acute adverse events will be graded and recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The incidence of grade 3-4 acute adverse events will be summarized by treatment arm.

Time frame: From the start of study treatment to 30 days after completion of neoadjuvant treatment.