Neoadjuvant Immunotherapy ± Radiotherapy in MSI-H/dMMR Locally Advanced Colorectal Cancer

Phase 2Not Yet RecruitingNCT07403877

Fudan University114 enrolled

Overview

This phase II clinical trial evaluates the efficacy and safety of three neoadjuvant regimens in patients with locally advanced microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC): 1) Regimen A: Dual immune checkpoint blockade with nivolumab plus ipilimumab. 2) Regimen B: Nivolumab plus radiotherapy. 3) Regimen C: Nivolumab monotherapy. The primary objectives are to determine whether: 1) Dual immune checkpoint blockade (Regimen A) is superior to nivolumab monotherapy (Regimen C); and 2) Immunotherapy plus radiotherapy (Regimen B) is superior to nivolumab monotherapy (Regimen C). Methods: Participants will be randomized in a 1:1:1 ratio to one of the three arms. For patients with resectable tumors, surgical resection will be performed. In patients with low rectal cancer and poor prospects for sphincter preservation, a watch-and-wait (WW) strategy is an option if a clinical complete response (CR) is achieved following neoadjuvant therapy.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

114

Conditions

Colorectal Cancer (MSI-H)

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Histopathologically confirmed primary colorectal adenocarcinoma. 2. Radiographic assessment showed a stage II-III based on AJCC Stage 8th ed. 3. At least 18 years old. 4. MSI-H or dMMR. 5. The Eastern Cooperative Oncology Group performance status (ECOG PS) score is 0 or 1. 6. Physical state or organ function can tolerate the planned treatment of the study protocol. 7. Agreed to sign written informed consent before recruitment. Exclusion Criteria: 1. Previously received any antitumor therapy for the disease under study, including surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc. 2. Pregnancy or breastfeeding women. 3. History of other malignancies within 5 years. 4. Serious medical illness, such as severe mental disorders, cardiac disease, uncontrolled infection, etc. 5. Immunodeficiency disease or long-term using of immunosuppressive agents. 6. Allergic to any component of the therapy. 7. Any other condition or disease that is not suitable to take the therapy included in the protocol. 8. Concurrent participation in another clinical study, unless participating in an observational (non-interventional) clinical study or in the survival follow-up phase of an interventional study. 9. Received any investigational drug or device treatment within 4 weeks prior to initial administration of the investigational drug.

Outcomes

Primary Outcomes

Complete regression (CR) rate

Proportion of patients achieving either clinical CR (and undergoing WW) or pathological CR (confirmed by pathology) among all evaluable patients.

Time frame: 1 month after surgery or the completion of neoadjuvant therapy

Secondary Outcomes

R0 resection rate

Proportion of patients who achieve R0 resection.

Time frame: 1 month after surgery

Objective response rate (ORR)

Proportion of patients with complete response (CR) or partial response (PR) to preoperative multimodal therapy. ORR will be evaluated using RESIST1.1 by CT/MRI of the chest, abdomen, and pelvis.

Time frame: 6 months after the enrollment of the last subject

Event-free survival (EFS)

The EFS was defined as the time from randomization to the first determination of inoperable disease progression, postoperative local recurrence or distant metastasis, tumor regrowth, or death from any cause, whichever occurs first.

Time frame: 36 months after the enrollment of the last subject

Overall survival (OS)

OS is defined as the time interval from enrollment to death of any reason or censoring.

Time frame: 36 months after the enrollment of the last subject

Toxicities

Number of participants with treatment-related adverse events (TrAEs) reported between the first dose and 28 days after the last dose of study therapy as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.

Time frame: From the time of enrollment, assessed up to 28 days after the last dose of study therapy

Surgical morbidity

Surgery related adverse events (SRAEs) refer to complications which happen during or one month after surgery. Severe complications after surgery will be documented and classified by Clavien-Dindo classification, such as abdominal or GI tract bleeding, anastomotic fistula, pancreatic fistula of grade B or above, and incision complications (infection, bleeding, rupture).

Time frame: During or one month after surgery

Surgical mortality

Death from any cause within 30 days of the date of surgery will be considered a surgical mortality death.