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

Phase 2RecruitingNCT03026140

The Netherlands Cancer Institute353 enrolled

Overview

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.

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. Accrual was reached for cohort 8 in February 2026. As February 2026 only cohorts 5 and 7 are open for recruitment. This also means that patients with dMMR/MSI tumors will no longer be randomized but automatically be registered in cohort 7 (and receive 3 cycles of nivolumab + relatlimab).

Study Type

INTERVENTIONAL

Conditions

Colon Carcinoma

Interventions

NivolumabDRUG

Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery

IpilimumabDRUG

Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery

Celecoxib 200mgDRUG

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)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (6)

Marieke van de Belt

Amsterdam, Netherlands

RECRUITING

OLVG

Amsterdam, Netherlands

RECRUITING

Catharina Ziekenhuis

Eindhoven, Netherlands

RECRUITING

Outcomes

Primary Outcomes

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.

Time frame: 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

Time frame: until 5 years after diagnosis

Major Pathological Response

To assess efficacy of neoadjuvant nivolumab monotherapy and neoadjuvant nivolumab plus relatlimab in terms of major pathologic response

Time frame: From date of randomization until the date of first documented progression, assessed up to 63 months

Secondary Outcomes

Immune activating capacity of short-term pre-operative immunotherapy

identify underlying potential escape mechanisms by comparing pre-treatment and post-treatment biopsies

Time frame: within 2 years after study completion

Relapse free survival

Time frame: 3-5 years after last patient inclusion.

Central Contacts

Marieke van de Belt

CONTACT

+3120512 m.vd.belt@nki.nl

Data from ClinicalTrials.gov

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