Neoadjuvant Immune Checkpoint Inhibition and Novel IO Combinations in Early-stage Colon Cancer
NCT ID: NCT03026140
Last Updated: 2025-09-19
Study Results
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Basic Information
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RECRUITING
PHASE2
353 participants
INTERVENTIONAL
2017-03-29
2032-03-01
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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group 1 - closed
drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV)
Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
Ipilimumab
Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery
group 2 - closed
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)
Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
Ipilimumab
Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery
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)
Anti-IL8 cohort 4 (pMMR/MSS tumors) - closed
drug: nivolumab 3 mg/kg day 1 and day 15 (IV) drug: BMS-986253 (anti-IL8) 2400mg on day 1 and day 15 (IV)
Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
BMS-986253
BMS-986253 2400mg IV will be administered on day 1 and 15 (only applicable for patients with MSS tumors)
Relatlimab cohort 5 (pMMR/MSS tumors)
drug: nivolumab 240mg IV on day 1 and day 15 drug: relatlimab 240mg IV on day 1 and day 15
Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
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
Relatlimab cohort 6 (dMMR/MSI tumors) - closed
drug: nivolumab 480mg IV on day 1 and day 29 drug: relatlimab 480mg IV on day 1 and day 29
Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
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
Cohort 7 - dMMR - 3 cycles neoadjuvant nivolumab + relatlimab
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
Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
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
Cohort 8 - dMMR - 3 cycles neoadjuvant nivolumab
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.
Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
Interventions
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Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
Ipilimumab
Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery
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)
BMS-986253
BMS-986253 2400mg IV will be administered on day 1 and 15 (only applicable for patients with MSS tumors)
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
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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 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
18 Years
ALL
No
Sponsors
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Bristol-Myers Squibb
INDUSTRY
The Netherlands Cancer Institute
OTHER
Responsible Party
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Principal Investigators
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Myriam Chalabi, MD
Role: PRINCIPAL_INVESTIGATOR
Antoni van Leeuwenhoek
Locations
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Marieke van de Belt
Amsterdam, , Netherlands
OLVG
Amsterdam, , Netherlands
Catharina Ziekenhuis
Eindhoven, , Netherlands
Spaarne Ziekenhuis
Haarlem, , Netherlands
Tergooi
Hilversum, , Netherlands
Haga ziekenhuis
The Hague, , Netherlands
Countries
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Central Contacts
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Facility Contacts
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A van Lent
Role: primary
P Burger
Role: primary
S Oosterling
Role: primary
E. Hendriks
Role: primary
T Aukema
Role: primary
References
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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 Oct 20. doi: 10.1038/s41586-025-09679-4. Online ahead of print.
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 Med. 2024 Nov;30(11):3284-3290. doi: 10.1038/s41591-024-03250-w. Epub 2024 Sep 15.
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.
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 Engl J Med. 2024 Jun 6;390(21):1949-1958. doi: 10.1056/NEJMoa2400634.
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.
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 in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020 Apr;26(4):566-576. doi: 10.1038/s41591-020-0805-8. Epub 2020 Apr 6.
Other Identifiers
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2024-513314-35-00
Identifier Type: CTIS
Identifier Source: secondary_id
N16NCI
Identifier Type: -
Identifier Source: org_study_id
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