Tolecizumab Plus Chemoimmunotherapy for pMMR/MSS Locally Advanced Colon Adenocarcinoma

Phase 2RecruitingNCT07468630

Daping Hospital and the Research Institute of Surgery of the Third Military Medical University106 enrolled

Overview

This multicenter, randomized, open-label, blinded-endpoint Phase II trial assesses the efficacy and safety of tolecizumab (PCSK9 inhibitor) plus sintilimab/CapeOX chemoimmunotherapy as neoadjuvant treatment for pMMR/MSS locally advanced colon adenocarcinoma (cT3c+). 106 patients are 1:1 randomized to the combination or chemoimmunotherapy alone, with pCR as the primary endpoint.

This is a multicenter, randomized, open-label, blinded-endpoint Phase II clinical trial designed to evaluate the efficacy and safety of tolecizumab (a PCSK9 inhibitor) combined with chemoimmunotherapy (sintilimab plus CapeOX regimen) as neoadjuvant treatment for patients with pMMR/MSS locally advanced colon adenocarcinoma (cT3c stage or above). A total of 106 eligible patients will be randomized 1:1 into two arms: Arm A (tolecizumab + sintilimab + CapeOX) and Arm B (sintilimab + CapeOX), both receiving 4 cycles of neoadjuvant therapy. The primary endpoint is the pathological complete response rate (pCR) after treatment; secondary endpoints include major pathological response rate (MPR), objective response rate (ORR), R0 resection rate, progression-free survival (PFS), overall survival (OS), and the incidence of adverse events (AEs) graded by NCI-CTCAE V5.0. A virtual historical control (single-agent CapeOX neoadjuvant chemotherapy) is set only for sample size calculation. The study will conduct safety follow-up for up to 90 days after the last administration and survival follow-up every 3 months for a total of 3 years, and also collect biological samples for exploratory biomarker analysis to explore the predictive factors of treatment efficacy. All study drugs and related examinations are provided free of charge for participants, and a Data and Safety Monitoring Board (DSMB) is established to monitor the study process and ensure participant safety.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Interventions

Tolecizumab (PCSK9 Inhibitor)DRUG

Tolecizumab (PCSK9 Inhibitor) 600mg, subcutaneous injection, Q6W (Weeks 1,7), 2 doses total Sintilimab (PD-1 Inhibitor) 200mg, intravenous infusion, Q3W (Weeks1,4,7,10), 4 cycles total CapeOX Regimen (Oxaliplatin + Capecitabine) Oxaliplatin 130mg/m² IV Q3W (4 cycles); Capecitabine 1000mg/m² oral twice daily, Days1-14 per cycle

SintilimabDRUG

1. Oxaliplatin: 130mg/m² intravenous infusion, Q3W at Week 1,4,7,10, total 4 cycles; 2. Capecitabine: 1000mg/m² oral administration, twice daily, Days 1-14 of each chemotherapy cycle. All drugs free of charge. 2. Sintilimab 200mg intravenous infusion, administered every 3 weeks (Q3W) at Week 1, 4, 7, 10, total 4 cycles; provided free of charge by the sponsor, used for neoadjuvant immunotherapy.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Signed the written informed consent form and voluntarily participate in the study. Pathohistologically confirmed colon adenocarcinoma with cT3c stage or above. Aged 18 to 80 years, regardless of gender. The lower edge of the tumor is more than 10 cm from the anus. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Sufficient bone marrow, liver, kidney and coagulation functions assessed by laboratory tests (in accordance with the local laboratory reference range). No previous anti-tumor treatment for the current colon cancer (including radiotherapy, chemotherapy, surgery, etc.). No pregnancy or lactation for female patients; male patients agree to take effective contraceptive measures during the study. Exclusion Criteria: * Previous anti-tumor treatment for the current colon cancer. Previous use of PCSK9 inhibitors or PD-1/PD-L1 inhibitors. Active autoimmune diseases or a history of autoimmune diseases. Receiving immunosuppressant or systemic glucocorticoid therapy (except for local low-dose glucocorticoid use). Active infection requiring systemic anti-infective treatment. Severe cardiovascular diseases (e.g., severe hypertension, myocardial infarction, heart failure, etc.). Complicated primary tumor (e.g., tumor perforation, intestinal obstruction without relief after intervention). Pregnant or lactating women. Other conditions that the investigator deems unfit for participation in the study (e.g., poor compliance, severe organ dysfunction, etc.).

Outcomes

Primary Outcomes

pCR

pCR was defined as the absence, from surgical samples, of malignant cells in the primary site and regional lymph nodes

Time frame: The pCR rate will be evaluated after surgery, an average of 12 weeks

Secondary Outcomes

Disease-free survival

Defined as the time from randomization to relapse or death, whichever occurred first.

Time frame: 3 years

Overall survival (OS)

Defined as the time from randomization to date of death due to any cause according to RECIST version 1.1 recorded in the time period between randomization and disease progression or death to any cause

Time frame: 3 years

MPR

After neoadjuvant therapy, the percentage of residual viable tumor cells in the tumor bed ≤ 10%. Regardless of whether there are viable tumor cells left in the lymph nodes

Time frame: From enrollment to 12 Weeks of treatment end

Curative resection

Curative resection defined as complete tumor resection with all margins being negative.

Time frame: Surgical operation assessment

Primary tumor downstaging rate

Down-staging of the resected tumour as measured by histopathological tumour diameter and stage according to the TNM staging system of AJCC (9th version).

Time frame: From enrollment to 12 Weeks of treatment end

Objective Response Rate (ORR)

Objective response is defined as a complete response (CR) or response (PR) according to RECIST v1.1

Time frame: After 4 cycles of neoadjuvant therapy (10 weeks)