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

Phase 2

Recruiting

• Conditions: Colon Carcinoma
• Interventions: Drug: Nivolumab; Drug: BMS-986016; Drug: Ipilimumab; Drug: BMS-986253; Drug: Celecoxib 200mg

• Registration Number: NCT03026140
• Lead Sponsor: The Netherlands Cancer Institute

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.

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.

Study Timeline

• Study First Submitted: 2016-12-15
• Study First Submitted QC: 2017-01-19
• Study First Posted: 2017-01-20
• Study Start: 2017-03-29
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-16
• Last Update Posted: 2024-04-18
• Primary Completion: 2024-12
• Study Completion: 2024-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 268

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
group 1 - closed	Nivolumab	drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV)
group 2 - closed	Nivolumab	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)
group 2 - closed	Celecoxib 200mg	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)
Relatlimab cohort 6 (dMMR/MSI tumors) - closed	BMS-986016	drug: nivolumab 480mg IV on day 1 and day 29 drug: relatlimab 480mg IV on day 1 and day 29
group 2 - closed	Ipilimumab	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)
Relatlimab cohort 5 (pMMR/MSS tumors)	BMS-986016	drug: nivolumab 240mg IV on day 1 and day 15 drug: relatlimab 240mg IV on day 1 and day 15
Relatlimab cohort 6 (dMMR/MSI tumors) - closed	Nivolumab	drug: nivolumab 480mg IV on day 1 and day 29 drug: relatlimab 480mg IV on day 1 and day 29
Anti-IL8 cohort 4 (pMMR/MSS tumors) - closed	BMS-986253	drug: nivolumab 3 mg/kg day 1 and day 15 (IV) drug: BMS-986253 (anti-IL8) 2400mg on day 1 and day 15 (IV)
group 1 - closed	Ipilimumab	drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV)
Anti-IL8 cohort 4 (pMMR/MSS tumors) - closed	Nivolumab	drug: nivolumab 3 mg/kg day 1 and day 15 (IV) drug: BMS-986253 (anti-IL8) 2400mg on day 1 and day 15 (IV)
Relatlimab cohort 5 (pMMR/MSS tumors)	Nivolumab	drug: nivolumab 240mg IV on day 1 and day 15 drug: relatlimab 240mg IV on day 1 and day 15

Primary Outcome Measures

Name	Time	Method
Disease free survival	until 5 years after diagnosis	To assess efficacy of neoadjuvant ipilimumab plus nivolumab in terms of disease-free survival
Incidence of adverse events during the treatment and follow-up (safety)	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.

Secondary Outcome Measures

Name	Time	Method
Relapse free survival	3-5 years after last patient inclusion.
Immune activating capacity of short-term pre-operative immunotherapy	within 2 years after study completion	identify underlying potential escape mechanisms by comparing pre-treatment and post-treatment biopsies

Trial Locations

Locations (6)

Marieke van de Belt; 🇳🇱 Amsterdam, Netherlands

Catharina Ziekenhuis; 🇳🇱 Eindhoven, Netherlands

Spaarne Ziekenhuis; 🇳🇱 Haarlem, Netherlands

Tergooi; 🇳🇱 Hilversum, Netherlands

Haga ziekenhuis; 🇳🇱 Den Haag, Netherlands

OLVG; 🇳🇱 Amsterdam, Netherlands