Clinical trial NCT03026140: Neoadjuvant Immune Checkpoint Inhibition and Novel IO Combinations in Early-stage Colon Cancer
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Colon Carcinoma
Keywords: MSI tumors
MSS tumors
short-term immunotherapy
surgical resection
nivolumab
ipilimumab
COX2
Anti-IL8
Relatlimab
Anti-LAG3
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2017-01-20
Enrollment: 268
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Incidence of adverse events during the treatment and follow-up (safety)
timeFrame: until 100 days after last patient last study drug treatment
measure: Disease free survival
timeFrame: until 5 years after diagnosis
Secondary outcomes:
measure: Immune activating capacity of short-term pre-operative immunotherapy
timeFrame: within 2 years after study completion
measure: Relapse free survival
timeFrame: 3-5 years after last patient inclusion.
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Marieke van de Belt
city: Amsterdam
country: Netherlands
facility: OLVG
city: Den Haag
country: Netherlands
facility: Haga ziekenhuis
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Haarlem
country: Netherlands
facility: Spaarne Ziekenhuis
city: Hilversum
country: Netherlands
facility: Tergooi
Study officials:
affiliation: Antoni van Leeuwenhoek
name: Myriam Chalabi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.