初期段階の結腸癌におけるニボルマブ、イピリムマブ、および COX2 阻害：感受性のシグナルに対する偏りのないアプローチ (NICHE)
初期段階の結腸癌におけるニボルマブ、イピリムマブ、および COX2 阻害: 感受性のシグナルに対する偏りのないアプローチ: ニッチ トライアル
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.
調査の概要
状態
状態
条件
条件
介入・治療
介入・治療
詳細な説明
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).
研究の種類
研究の種類
入学 (推定)
入学
段階
段階
- フェーズ2
連絡先と場所
研究連絡先
研究連絡先
- 名前：Marieke van de Belt
- 電話番号：1926 +3120512
- メール：m.vd.belt@nki.nl
研究場所
-
-
-
Amsterdam、オランダ
- 募集
- OLVG
-
コンタクト：
- A van Lent
-
Amsterdam、オランダ、1066CX
- 募集
- Marieke van de Belt
-
コンタクト：
- Marieke van de Belt
- 電話番号：1926 +3120512
- メール：m.vd.belt@nki.nl
-
Eindhoven、オランダ
- 募集
- Catharina Ziekenhuis
-
コンタクト：
- P Burger
-
Haarlem、オランダ
- 募集
- Spaarne Ziekenhuis
-
コンタクト：
- S Oosterling
-
Hilversum、オランダ
- まだ募集していません
- Tergooi
-
コンタクト：
- E. Hendriks
-
The Hague、オランダ
- まだ募集していません
- Haga ziekenhuis
-
コンタクト：
- T Aukema
-
-
参加基準
適格基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
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
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
アーム数
武器と介入
参加者グループ / アーム参加者グループ / アーム |
介入・治療介入・治療 |
|---|---|
|
実験的：group 1 - closed
drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV) |
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
他の名前：
Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery
他の名前：
|
|
実験的：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 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
他の名前：
Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery
他の名前：
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)
他の名前：
|
|
実験的：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 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
他の名前：
BMS-986253 2400mg IV will be administered on day 1 and 15 (only applicable for patients with MSS tumors)
他の名前：
|
|
実験的：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 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
他の名前：
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
他の名前：
|
|
実験的：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 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
他の名前：
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
他の名前：
|
|
実験的：Cohort 7 - dMMR - 3 cycles neoadjuvant nivolumab + relatlimab - closed
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 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
他の名前：
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
他の名前：
|
|
実験的：Cohort 8 - dMMR - 3 cycles neoadjuvant nivolumab - closed
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 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Incidence of adverse events during the treatment and follow-up (safety)
時間枠：until 100 days after last patient last study drug treatment
|
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
時間枠：until 5 years after diagnosis
|
To assess efficacy of neoadjuvant ipilimumab plus nivolumab in terms of disease-free survival |
until 5 years after diagnosis
|
|
Major Pathological Response
時間枠：From date of randomization until the date of first documented progression, assessed up to 63 months
|
To assess efficacy of neoadjuvant nivolumab monotherapy and neoadjuvant nivolumab plus relatlimab in terms of major pathologic response |
From date of randomization until the date of first documented progression, assessed up to 63 months
|
二次結果の測定
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
無再発生存
時間枠：最後の患者登録から 3 ～ 5 年。
|
最後の患者登録から 3 ～ 5 年。
|
|
|
Immune activating capacity of short-term pre-operative immunotherapy
時間枠：within 2 years after study completion
|
identify underlying potential escape mechanisms by comparing pre-treatment and post-treatment biopsies |
within 2 years after study completion
|
協力者と研究者
協力者
協力者
捜査官
捜査官
- 主任研究者：Myriam Chalabi, MD、Antoni van Leeuwenhoek
出版物と役立つリンク
一般刊行物
- 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.
- 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.
- 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.
- Chalabi M, van den Dungen LDW, de Gooyer PGM, Balduzzi S, Aalbers AGJ, Kerver ED, Grootscholten C, Dokter S, Bloemen JG, Hendriks ER, Aukema TS, Oosterling SJ, Verbeek WHM, Voest EE, Kok NFM, Foppen MHG, Beets-Tan RG, Tin A, Jurdi A, Schumacher TN, van Leerdam ME, van den Berg JG, Haanen JBAG. Disease-free survival and overall survival after neoadjuvant immunotherapy in mismatch repair-deficient colon cancer in the Netherlands: results of the single-arm, multicentre, phase 2, NICHE-2 trial. Lancet. 2026 Oct 21:S0140-6736(26)01602-8. doi: 10.1016/S0140-6736(26)01602-8. Online ahead of print.
研究記録日
主要日程の研究
研究開始 (実際)
研究開始
一次修了 (推定)
一次修了
研究の完了 (推定)
研究の完了
試験登録日
最初に提出
最初に提出
QC基準を満たした最初の提出物
QC基準を満たした最初の提出物
最初の投稿 (推定)
最初の投稿
学習記録の更新
投稿された最後の更新 (実際)
投稿された最後の更新
QC基準を満たした最後の更新が送信されました
QC基準を満たした最後の更新が送信されました
最終確認日
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
- 部位別新生物
- 新生物
- 腸の病気
- 消化器腫瘍
- 消化器系腫瘍
- 消化器系疾患
- 消化器疾患
- 結腸直腸腫瘍
- 腸の腫瘍
- 結腸疾患
- 結腸新生物
- アミノ酸、ペプチド、およびタンパク質
- タンパク質
- 硫黄化合物
- 有機化学物質
- 複素環化化合物、1リング
- 複素環化化合物
- アゾール
- 炭化水素
- 炭化水素、周期的
- 炭化水素、芳香
- アミド
- 抗体、モノクローナル、ヒト化
- 抗体、モノクローナル
- 抗体
- 免疫グロブリン
- 免疫タンパク質
- 血液タンパク質
- 血清グロブリン
- グロブリン
- ベンゼン誘導体
- ベンゼンスルホンアミド
- スルホンアミド
- スルホン
- ピラゾール
- ニボルマブ
- セレコキシブ
- イピリムマブ
- relatlimab
- Humax-IL8
その他の研究ID番号
その他の研究ID番号
- N16NCI
- 2024-513314-35-00 (Ctis)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。