Envafolimab as Neoadjuvant Immuntherapy in Resectable Local Advanced dMMR/MSI-H Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
Colorectal cancer (CRC) is one of the most common malignant tumours of human beings. Mismatch Repair-deficient (dMMR)/ Microsatellite Instability-high (MSI-H) CRC is a specific subtype of CRC, which accounts for approximately 15% of all CRC patients, and can not benefit from 5-fluorouracil (5-FU) adjuvant chemotherapy. Once patients have distant metastases, they are not sensitive to traditional palliative chemotherapy, and thus lead to much worse prognosis than that of mismatch repair-proficient (pMMR)/ microsatellite stability (MSS). A phase II clinical study of anti-PD-1 immunotherapy based on mismatch repair (MMR) status published in N Engl J Med showed that the objective response rate (ORR) of advanced colorectal cancer patients with dMMR received anti-PD-1 is 40%, and a longer response time can be obtained compared to conventional chemotherapy. Another study (ClinicalTrials.gov, NCT03926338) which investigating the effect of neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, on mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer. The result revealed that all 34 patients had an R0 resection. 15 of 17 patients (88%) in the toripalimab plus celecoxib group and 11 of 17 patients (65%) in the toripalimab monotherapy group had a pathological complete response. In theory, anti-PD-L1 drugs should have fewer immune side-effects than anti-PD-1 drugs. However, there are no reports of anti-PD-L1 neoadjuvant therapy for the dMMR/MSI-H colorectal cancer. Therefore, the aim of this study was to investigate the efficacy and safety of anti-PD-L1 monoclonal antibody (Envafolimab) as neoadjuvant immuntherapy for resectable local advanced colorectal cancer patient with the dMMR/MSI-H.

Official Title
-----------------
Envafolimab as Neoadjuvant Immuntherapy in Resectable Local Advanced dMMR/MSI-H Colorectal Cancer

Conditions
-----------------
Colorectal Cancer, Mismatch Repair-deficient (dMMR), Microsatellite Instability-high (MSI-H), Neoadjuvant Therapy

Intervention / Treatment
-----------------
* Drug: Neoadjuvant therapy with PD-L1 inhibitor


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Willing and able to provide written informed consent. Histological or cytological documentation of adenocarcinoma of the colon or rectum. Tumor tissues were identified as mismatch repair-deficient (dMMR) by immunohistochemistry (IHC) method or microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR). Male or female subjects > 18 years < 70 of age. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Determined CT or MRI scans (done within 14 days of registration) of the chest, abdomen and pelvis: locally advanced (cT3-4 or cN1-2 [with the definition of a clinically positive lymph node being any node ≥ 1.0 cm]). Non complicated primary tumor (obstruction, perforation, bleeding). No previous any systemic anticancer therapy for colorectal cancer disease or radiologic evaluation of tumor regression < 20% or unacceptable toxic effects during neoadjuvant chemotherapy. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment. Exclusion Criteria: Previous or concurrent cancer that is distinct in primary site or histology from colon cancer within 5 years prior to randomization. Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment. Heart failure grade III/IV (NYHA-classification). Unresolved toxicity higher than CTCAE v.4.0 Grade 1 attributed to any prior therapy/procedure. Subjects with known allergy to the study drugs or to any of its excipients. Current or recent (within 4 weeks prior to starting study treatment) treatment of another investigational drug or participation in another investigational study. Breast- feeding or pregnant women Lack of effective contraception. Previously received anti-programmed death-1 (PD-1) or its ligand (PD-L1) antibody, anti-cytotoxic T lymphocyte-associated antigen 4 (cytotoxic T-lymphocyte-associated Protein 4, CTLA-4) antibody or other drug/antibody that acts on T cell costimulation or checkpoint pathways. With any distant metastasis.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PD-L1 inhibitor<br>Neoadjuvant therapy with PD-L1 inhibitor (Envafolimab) | Drug: Neoadjuvant therapy with PD-L1 inhibitor<br>* Neoadjuvant therapy with PD-L1 inhibitor (Envafolimab), 300mg, Q3W for 4 cycles<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (pCR) rates | Proportion of patients experiencing a pCR to perioperative PD-L1 antibody | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major pathological response rates | The proportion of patients experiencing a major pathological response to perioperative PD-L1 antibody | 1 year | 
| R0 resection rates | The proportion of patients experiencing a R0 resection after perioperative treatment with PD-L1 antibody | 1 year | 
| Disease-free survival (DFS) | Defined as the time from randomization to relapse, metastasis or death from any cause | 3 years | 
| Overall survival (OS) | Defined as the time from randomization to death from any cause | 5 years | 
| Drug Safety | Assessed by evaluation of treatment-related adverse events | 1 year | 
| Drug feasibility | Any treatment-related delays in the planned surgery of no more than 28 days after the last preoperative toripalimab dose | 1 year |