Toripalimab With or Without Celecoxib as Neoadjuvant Therapy in Resectable dMMR/MSI-H Colorectal Cancer

Study Overview
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Brief Summary
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Colorectal cancer of Mismatch Repair-deficient (dMMR)/ Microsatellite Instability-high (MSI-H) accounts for approximately 15% of all colorectal cancer patients, with a higher proportion in right colon cancer. Previous studies have found that colon cancer patients with dMMR/MSI-H cannot benefit from 5-fluorouracil (5-FU) adjuvant chemotherapy. Once patients have distant metastases, they are not sensitive to traditional palliative chemotherapy, and the prognosis is significantly worse 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. Anti-PD-1 neoadjuvant therapy has proven to be safe and feasible in lung cancer, bladder cancer and malignant melanoma, and can achieve more than 40% of major pathological response. However, there are no reports of anti-PD-1 neoadjuvant therapy for the dMMR/MSI-H colorectal cancer. Therefore, the aim of this study was to find the best multidisciplinary treatment for resectable colorectal cancer patient with the dMMR/MSI-H phenotype and to explore whether cyclooxygenase (COX) inhibitors combined with anti-PD-1 monoclonal antibody (mAb) could further improve efficacy.

Official Title
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A Pilot Study of Toripalimab With or Without Celecoxib as Neoadjuvant Therapy in Resectable Non-metastatic Colorectal Cancer Patients With Mismatch Repair-deficient or Microsatellite Instability-high

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

Intervention / Treatment
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* Drug: Neoadjuvant therapy with PD-1 inhibitor plus COX inhibitor
* Drug: Neoadjuvant therapy with PD-1 inhibitor


Participation Criteria
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Eligibility Criteria
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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 ≦ 75 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
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PD-1 inhibitor plus COX inhibitor<br>Neoadjuvant therapy with PD-1 inhibitor (Toripalimab) plus COX inhibitor (Celecoxib) | Drug: Neoadjuvant therapy with PD-1 inhibitor plus COX inhibitor<br>* Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 3 months or 6 months) and Celecoxib (oral 200mg twice daily for 3 months or 6 months) followed by colectomy. The choice of treatment duration of 3 months or 6 months was made by the treating physician and patient before randomization.<br>* Other names: Celecoxib;|
| Experimental: PD-1 inhibitor<br>Neoadjuvant therapy with PD-1 inhibitor (Toripalimab) | Drug: Neoadjuvant therapy with PD-1 inhibitor<br>* Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 3 months or 6 months) followed by colectomy. The choice of treatment duration of 3 months or 6 months was made by the treating physician and patient before randomization.<br>* Other names: Toripalimab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival (DFS) | Defined as the time from randomization to relapse, metastasis or death from any cause. | 3 years | 
| Pathological complete response (pCR) rates | Proportion of patients experiencing a pCR to perioperative PD-1 antibody in each group | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Defined as the time from randomization to death from any cause. | 5 years | 
| R0 resection rates | The proportion of patients achieved a complete resection with negative margin. | 1 years | 
| Surgical and perioperative treatment safety | Assessed by evaluation of treatment-related adverse events | 1 years | 
| Surgery feasibility | Any treatment-related delays in the planned surgery of no more than 28 days after the last preoperative toripalimab dose | 90 days after surgery |