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

Official title

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)

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.

Detailed 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.

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).

Interventions

• Drug Nivolumab
  Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
• Drug Ipilimumab
  Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery
• Drug Celecoxib 200mg
  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)
• Drug BMS-986253
  BMS-986253 2400mg IV will be administered on day 1 and 15 (only applicable for patients with MSS tumors)
• Drug BMS-986016
  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, in cohort 7 160mg on day 1, day 29 and day 57

Primary outcome measures

• Incidence of adverse events during the treatment and follow-up (safety) [Time frame: until 100 days after last patient last study drug treatment]
• Disease free survival [Time frame: until 5 years after diagnosis]
• Major Pathological Response [Time frame: From date of randomization until the date of first documented progression, assessed up to 63 months]

Secondary outcome measures (2)

• Immune activating capacity of short-term pre-operative immunotherapy [Time frame: within 2 years after study completion]
• Relapse free survival [Time frame: 3-5 years after last patient inclusion.]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Netherlands · 6 centers

• Marieke van de Belt — Amsterdam
• OLVG — Amsterdam
• Catharina Ziekenhuis — Eindhoven
• Spaarne Ziekenhuis — Haarlem
• Tergooi — Hilversum
• Haga ziekenhuis — The Hague

Publications

• Tan PB, Verschoor YL, van den Berg JG, Balduzzi S, Kok NFM, Ijsselsteijn ME, Moore K, Jurdi A, Tin A, Kaptein P, van Leerdam ME, Haanen JBAG, Voest EE, de Miranda NFCC, Schumacher TN, Wessels LFA, Chalabi M. Neoadjuvant immunotherapy in mismatch-repair-proficient colon cancers. Nature. 2025 Dec;648(8094):726-735. doi: 10.1038/s41586-025-09679-4. Epub 2025 Oct 20. PMID 41115454
• de Gooyer PGM, Verschoor YL, van den Dungen LDW, Balduzzi S, Marsman HA, Geukes Foppen MH, Grootscholten C, Dokter S, den Hartog AG, Verbeek WHM, Woensdregt K, van den Broek JJ, Oosterling SJ, Schumacher TN, Kuhlmann KFD, Beets-Tan RGH, Haanen JBAG, van Leerdam ME, van den Berg JG, Chalabi M. Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial. Nat PMID 39278994
• Cercek A. Neoadjuvant Treatment of Mismatch Repair-Deficient Colon Cancer - Clinically Meaningful? N Engl J Med. 2024 Jun 6;390(21):2024-2025. doi: 10.1056/NEJMe2404601. No abstract available. PMID 38838316
• Chalabi M, Verschoor YL, Tan PB, Balduzzi S, Van Lent AU, Grootscholten C, Dokter S, Buller NV, Grotenhuis BA, Kuhlmann K, Burger JW, Huibregtse IL, Aukema TS, Hendriks ER, Oosterling SJ, Snaebjornsson P, Voest EE, Wessels LF, Beets-Tan RG, Van Leerdam ME, Schumacher TN, van den Berg JG, Beets GL, Haanen JB. Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair-Deficient Colon Cancer. N En PMID 38838311
• Wang D, Cabalag CS, Clemons NJ, DuBois RN. Cyclooxygenases and Prostaglandins in Tumor Immunology and Microenvironment of Gastrointestinal Cancer. Gastroenterology. 2021 Dec;161(6):1813-1829. doi: 10.1053/j.gastro.2021.09.059. Epub 2021 Oct 2. PMID 34606846
• Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, Lopez-Yurda M, Grootscholten C, Beets GL, Snaebjornsson P, Maas M, Mertz M, Veninga V, Bounova G, Broeks A, Beets-Tan RG, de Wijkerslooth TR, van Lent AU, Marsman HA, Nuijten E, Kok NF, Kuiper M, Verbeek WH, Kok M, Van Leerdam ME, Schumacher TN, Voest EE, Haanen JB. Neoadjuvant immunotherapy leads to pathological responses PMID 32251400

Identifiers

NCT: NCT03026140 · N16NCI · 2024-513314-35-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗