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

Netherlands Cancer Institute (NKI)

Status and phase: Enrolling; Phase 2

Conditions: Colon Carcinoma

Treatments: Drug: Nivolumab; Drug: BMS-986253; Drug: Celecoxib 200mg; Drug: BMS-986016; Drug: Ipilimumab

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03026140

N16NCI

2024-513314-35-00 (EU Trial (CTIS) Number)

Details and patient eligibility

About

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, anti-LAG3). This treatment will be given during the window period until surgical resection of the tumor. The duration of treatment will be in between approximately 6 and 12 weeks.

Full description

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.

Accrual for cohort 4 was reached in July 2023. In April 2024, accrual for cohort 6 was reached. Per April 2024 only cohort 5 is open for recruitment.

The study was amended in April 2025 to add cohort 7 and 8. Patients with dMMR/MSI tumors will be randomized 1:1 between cohort 7 and 8, in which they will receive 3 cycles of nivolumab + relatlimab or 3 cycles of nivolumab monotherapy respectively. Per June 2025, cohort 5, 7 and 8 are open for recruitment.

Enrollment: 353 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

353 participants in 7 patient groups

group 1 - closed

Experimental group

Description:

drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV)

Treatment:

Drug: Ipilimumab

Drug: Nivolumab

group 2 - closed

Experimental group

Description:

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)

Treatment:

Drug: Ipilimumab

Drug: Celecoxib 200mg

Drug: Nivolumab

Anti-IL8 cohort 4 (pMMR/MSS tumors) - closed

Experimental group

Description:

drug: nivolumab 3 mg/kg day 1 and day 15 (IV) drug: BMS-986253 (anti-IL8) 2400mg on day 1 and day 15 (IV)

Treatment:

Drug: BMS-986253

Drug: Nivolumab

Relatlimab cohort 5 (pMMR/MSS tumors)

Experimental group

Description:

drug: nivolumab 240mg IV on day 1 and day 15 drug: relatlimab 240mg IV on day 1 and day 15

Treatment:

Drug: BMS-986016

Drug: Nivolumab

Relatlimab cohort 6 (dMMR/MSI tumors) - closed

Experimental group

Description:

drug: nivolumab 480mg IV on day 1 and day 29 drug: relatlimab 480mg IV on day 1 and day 29

Treatment:

Drug: BMS-986016

Drug: Nivolumab

Cohort 7 - dMMR - 3 cycles neoadjuvant nivolumab + relatlimab

Experimental group

Description:

Patients with dMMR tumors will be treated with 3 cycles of neoadjuvant nivolumab (480mg) + relatlimab (160mg) on day 1, day 29 and day 57 followed by surgery within 12 weeks and not earlier than 10 weeks from enrollment

Treatment:

Drug: BMS-986016

Drug: Nivolumab

Cohort 8 - dMMR - 3 cycles neoadjuvant nivolumab

Experimental group

Description:

Patients with dMMR tumors will be treated with 3 cycles of neoadjuvant nivolumab (480mg) on day 1, day 29 and day 57 followed by surgery within 12 weeks and not earlier than 10 weeks from enrollment.

Treatment:

Drug: Nivolumab