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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03026140
Recruitment Status : Recruiting
First Posted : January 20, 2017
Last Update Posted : January 26, 2023
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
The Netherlands Cancer Institute

Study Description
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Brief Summary:
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). This treatment will be given during the window period until surgical resection of the tumor. The duration of treatment will be approximately 6 weeks.

Condition or disease Intervention/treatment Phase
Colon Carcinoma Drug: Nivolumab Drug: Ipilimumab Drug: Celecoxib 200mg Drug: BMS-986253 Drug: BMS-986016 Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 268 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : March 29, 2017
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: group 1
drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV)
 Drug: Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
Other Name: nivolumab (opdivo)

Drug: Ipilimumab
Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery
Other Name: Ipilimumab (Yervoy)
Experimental: group 2
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)
 Drug: Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
Other Name: nivolumab (opdivo)

Drug: Ipilimumab
Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery
Other Name: Ipilimumab (Yervoy)

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)
Other Name: Celebrex
Experimental: Anti-IL8 cohort 4 (pMMR/MSS tumors)
drug: nivolumab 3 mg/kg day 1 and day 15 (IV) drug: BMS-986253 (anti-IL8) 2400mg on day 1 and day 15 (IV)
 Drug: Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
Other Name: nivolumab (opdivo)

Drug: BMS-986253
BMS-986253 2400mg IV will be administered on day 1 and 15 (only applicable for patients with MSS tumors)
Other Name: Anti-IL8
Experimental: 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
 Drug: Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
Other Name: nivolumab (opdivo)

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
Other Name: Relatlimab
Experimental: Relatlimab cohort 6 (dMMR/MSI tumors)
drug: nivolumab 480mg IV on day 1 and day 29 drug: relatlimab 480mg IV on day 1 and day 29
 Drug: Nivolumab
Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
Other Name: nivolumab (opdivo)

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
Other Name: Relatlimab


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of adverse events during the treatment and follow-up (safety) [ Time Frame: 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.

  2. Disease free survival [ Time Frame: until 5 years after diagnosis ]
    To assess efficacy of neoadjuvant ipilimumab plus nivolumab in terms of disease-free survival


Secondary Outcome Measures :
  1. Immune activating capacity of short-term pre-operative immunotherapy [ Time Frame: within 2 years after study completion ]
    identify underlying potential escape mechanisms by comparing pre-treatment and post-treatment biopsies

  2. Relapse free survival [ Time Frame: 3-5 years after last patient inclusion. ]

Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03026140


Contacts
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Contact: Marieke van de Belt +3120512 ext 1926 m.vd.belt@nki.nl

Locations
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Netherlands
Marieke van de Belt Recruiting
Amsterdam, Netherlands, 1066CX
Contact: Marieke van de Belt    +3120512 ext 1926    m.vd.belt@nki.nl   
OLVG Recruiting
Amsterdam, Netherlands
Contact: A van Lent         
Haga ziekenhuis Not yet recruiting
Den Haag, Netherlands
Contact: T Aukema         
Catharina Ziekenhuis Recruiting
Eindhoven, Netherlands
Contact: P Burger         
Spaarne Ziekenhuis Recruiting
Haarlem, Netherlands
Contact: S Oosterling         
Tergooi Not yet recruiting
Hilversum, Netherlands
Contact: E. Hendriks         
Sponsors and Collaborators
The Netherlands Cancer Institute
Bristol-Myers Squibb
Investigators
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Principal Investigator: Myriam Chalabi, MD Antoni van Leeuwenhoek
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT03026140    
Other Study ID Numbers: N16NCI
First Posted: January 20, 2017    Key Record Dates
Last Update Posted: January 26, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by The Netherlands Cancer Institute:
MSI tumors
MSS tumors
short-term immunotherapy
surgical resection
nivolumab
 ipilimumab
COX2
Anti-IL8
Relatlimab
Anti-LAG3
Additional relevant MeSH terms:
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Colonic Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Celecoxib
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
 Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors