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

Colon Carcinoma Clinical Trial

— NICHE  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03026140
• Other study ID #: N16NCI
• Status: Recruiting
• Phase: Phase 2
• Start date: March 29, 2017
• Est. completion date: December 2024

Study information

• Verified date: April 2024
• Source: The Netherlands Cancer Institute
• Contact: Marieke van de Belt
• Phone: +3120512
• Email: m.vd.belt[@]nki.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 268
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colon Carcinoma
• Colonic Neoplasms

Intervention

Drug:
• 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

Locations

Country	Name	City	State
Netherlands	Marieke van de Belt	Amsterdam
Netherlands	OLVG	Amsterdam
Netherlands	Haga ziekenhuis	Den Haag
Netherlands	Catharina Ziekenhuis	Eindhoven
Netherlands	Spaarne Ziekenhuis	Haarlem
Netherlands	Tergooi	Hilversum

Sponsors (2)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	Bristol-Myers Squibb

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	until 100 days after last patient last study drug treatment
Primary	Disease free survival	To assess efficacy of neoadjuvant ipilimumab plus nivolumab in terms of disease-free survival	until 5 years after diagnosis
Secondary	Immune activating capacity of short-term pre-operative immunotherapy	identify underlying potential escape mechanisms by comparing pre-treatment and post-treatment biopsies	within 2 years after study completion
Secondary	Relapse free survival		3-5 years after last patient inclusion.