Neoadjuvant Immune Checkpoint Inhibition and Novel IO Combinations in Early-stage Colon Cancer

Study Overview
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Brief Summary
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In this exploratory study, patients with stage 1-3 adenocarcinoma of the colon with no signs of distant metastases will be treated with short-term immunotherapy + novel IO combinations (i.e. anti-IL 8, COX2-inhibitors). This treatment will be given during the window period until surgical resection of the tumor. The duration of treatment will be approximately 6 weeks.

Detailed Description
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In this multi-center, open-label, exploratory study, the investigators will enroll 60 patients within two years, including 30 patients with MSS tumors and 30 patients with MSI tumors. Patients with MSS tumors will be randomized to either group 1 or 2. Patients with MSI tumors will all be allocated to group 1. Patients in group 1 will be treated with a single dose of ipilimumab 1mg/kg on day 1 and two cycles of nivolumab 3mg/kg on day 1 and 15, respectively. Patients in group 2 will be treated with a single dose of ipilimumab 1mg/kg on day 1, two cycles of nivolumab 3mg/kg one day 1 and 15 and celecoxib daily until the day before surgery. The study was amended in May 2020 to enroll an additional 70 patients in the MSI cohort after the first 30 patients, making a total of 100 patients with MSI tumors. A formal sample size calculation and primary endpoint of 3-year disease-free-survival (DFS) for this group was added. The study was amended in July 2021 to add a new cohort, cohort 4, for patients with pMMR/MSS tumors. Once accrual of 30 evaluable patients in group 2 was completed, a new cohort opened in which patients will receive nivolumab plus anti-IL8 (BMS-986253). The study was amended in November 2022 to add cohort 5 and 6, both in which patients will receive nivolumab plus relatlimab (anti-LAG3). Patients with pMMR/MSS tumors will be randomized 1:1 between cohort 4 and cohort 5, patients with dMMR/MSI tumors will be enrolled in cohort 6.

Official Title
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Neoadjuvant Immune Checkpoint Inhibition and Novel IO Combinations in Early-stage Colon Cancer (Amended Protocol of: Nivolumab, Ipilimumab and COX2-inhibition in Early Stage Colon Cancer: an Unbiased Approach for Signals of Sensitivity: The NICHE TRIAL)

Conditions
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Colon Carcinoma

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Ipilimumab
* Drug: Celecoxib 200mg
* Drug: BMS-986253
* Drug: BMS-986016


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed written informed consent Patients at least 18 years of age Non-metastatic adenocarcinoma of the colon (and rectosigmoid considered as nonrectal and not undergoing neoadjuvant treatment) No signs of distant metastases on CT-scan and physical examination; dMMR cohorts 3+6: >cT3 and/or N+ Exclusion criteria: No signs of distant metastases No signs of obstruction or macroscopic bleeding or suspicion of perforation Colonoscopy must be performed after registration to obtain study-specific biopsies. If biopsies are not possible, patients cannot be included in the study WHO performance status of 0 or 1 No previous treatment with immune checkpoint inhibitors targeting CTLA-4, PD-1 or PD-L1 For patients with MSS tumors: no current use of NSAIDs or COX2-inhibitors at registration and no active peptic ulcer, gastrointestinal bleeding, unstable ischemic heart disease of thrombus etiology or significant established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease No radiotherapy prior to or planned post-surgery radiotherapy No history of allergy to study drug components, severe hypersensitivity reaction to any monoclonal antibody, allergy or severe hypersensitivity to NSAIDs or COX2-I (MSS tumors) No intercurrent illnesses, including but not limited to infections, unstable angina pectoris No positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection No autoimmune disease No conditions requiring systemic treatment with either corticosteroids (10 mg daily prednisone or more and equivalents) or other immunosuppressive medications within 14 days of study drug administration No live vaccines in the 4 weeks prior to inclusion

Ages Eligible for Study
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Minimum Age: 18 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: group 1<br>drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV) | Drug: Nivolumab<br>* Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery<br>* Other names: nivolumab (opdivo);Drug: Ipilimumab<br>* Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery<br>* Other names: Ipilimumab (Yervoy);|
| Experimental: group 2<br>drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV) drug: celecoxib 200 mg daily (oral) | Drug: Nivolumab<br>* Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery<br>* Other names: nivolumab (opdivo);Drug: Ipilimumab<br>* Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery<br>* Other names: Ipilimumab (Yervoy);Drug: Celecoxib 200mg<br>* celecoxib will be administered starting day 1 until 1 day before surgery daily (if patient is randomized to group 2 (only applicable for patients with a MSS tumor)<br>* Other names: Celebrex;|
| Experimental: Anti-IL8 cohort 4 (pMMR/MSS tumors)<br>drug: nivolumab 3 mg/kg day 1 and day 15 (IV) drug: BMS-986253 (anti-IL8) 2400mg on day 1 and day 15 (IV) | Drug: Nivolumab<br>* Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery<br>* Other names: nivolumab (opdivo);Drug: BMS-986253<br>* BMS-986253 2400mg IV will be administered on day 1 and 15 (only applicable for patients with MSS tumors)<br>* Other names: Anti-IL8;|
| Experimental: Relatlimab cohort 5 (pMMR/MSS tumors)<br>drug: nivolumab 240mg IV on day 1 and day 15 drug: relatlimab 240mg IV on day 1 and day 15 | Drug: Nivolumab<br>* Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery<br>* Other names: nivolumab (opdivo);Drug: BMS-986016<br>* Relatlimab will be administered IV, in cohort 5 240mg on day 1 and day 15, in cohort 6 480mg on day 1 and day 29<br>* Other names: Relatlimab;|
| Experimental: Relatlimab cohort 6 (dMMR/MSI tumors)<br>drug: nivolumab 480mg IV on day 1 and day 29 drug: relatlimab 480mg IV on day 1 and day 29 | Drug: Nivolumab<br>* Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery<br>* Other names: nivolumab (opdivo);Drug: BMS-986016<br>* Relatlimab will be administered IV, in cohort 5 240mg on day 1 and day 15, in cohort 6 480mg on day 1 and day 29<br>* Other names: Relatlimab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events during the treatment and follow-up (safety) | Adverse events will be assessed (according to CTCAE v4.0) during treatment and follow-up. | until 100 days after last patient last study drug treatment | 
| Disease free survival | To assess efficacy of neoadjuvant ipilimumab plus nivolumab in terms of disease-free survival | until 5 years after diagnosis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune activating capacity of short-term pre-operative immunotherapy | identify underlying potential escape mechanisms by comparing pre-treatment and post-treatment biopsies | within 2 years after study completion | 
| Relapse free survival |  | 3-5 years after last patient inclusion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MSI tumors, MSS tumors, short-term immunotherapy, surgical resection, nivolumab, ipilimumab, COX2, Anti-IL8, Relatlimab, Anti-LAG3