Neoadjuvant immune checkpoint inhibition and novel IO combinations in early-stage colon cancer - the NICHE trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Jan 2017 → ongoing

Decision date (initial)

2024-11-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-513314-35-00

EudraCT number

2016-002940-17

ClinicalTrials.gov

NCT03026140

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To determine the efficacy of neoadjuvant immunotherapy in patients with colon cancer

Secondary objectives 11

1. To assess the major pathological response rate (MPR, <10% viable tumor rest) and complete response rate
2. To find biomarkers and evaluation strategies able to accurately assess complete and nearcomplete responses in order to pursue organ-sparing treatment (omission of surgery) in this patient population
3. To expand current translational analyses in terms of RNA sequencing and inflammatory signatures, analysis of immune cell infiltration and transcriptomics, and ctDNA analysis
4. To assess the efficacy of nivolumab plus anti-IL8 and the predictive value of serum IL-8 in terms of pathological response
5. Analysis of immune cell infiltration and the difference with inflamed pMMR tumors pre- and post-treatment
6. To assess post-surgical outcome and infectious complications following neoadjuvant immunotherapy
7. To assess the immunogenic mutational load by DNA WES and correlation with putative markers of response
8. To assess event free survival and overall survival for the pMMR and dMMR cohorts (if not a primary objective)
9. To explore the immunogenicity and in vitro T-cell sensitivity of tumor organoid cultures and explore efficacy of novel treatment combinations for a selection of patients
10. Safety, evaluated by the incidence and severity of irAEs, SAEs and the frequency of delays of surgery >2 weeks from the intended date due to treatment related complications (if not a primary objective of the cohort)
11. To evaluate health-related quality of life through patient reported outcome measures

Conditions and MedDRA coding

Adenocarcinoma of the Colon or rectosigmoid (considered as non-rectal)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Signed written informed consent
2. Patients at least 18 years of age
3. Non-metastatic adenocarcinoma of the colon (and rectosigmoid considered as nonrectal and not undergoing neoadjuvant treatment)
4. dMMR cohorts 3+6: >cT3 and/or N+
5. Colonoscopy must be performed after informed consent to obtain study-specific biopsies. If biopsies are not possible, patients cannot be included in the study
6. WHO performance status of 0 or 1
7. Screening laboratory tests must meet the following criteria and should be obtained within 7 days prior to randomization/registration: WBC > 2.0 x 10^9/L, ANC > 1.5x10^9/L, platelets > 100 x 10^9/L, Hemoglobin > 5.0mmol/L. Transfusion is allowed to obtain an adequate hemoglobin level. Liver function tests: total bilirubin < 1.5 upper limit of normal (ULN) (except for subjects with Gilbert syndrome, who can have total bilirubin <3.0 mg/dL); alkaline phosphatase <2.5 ULN; transaminases (ASAT/ALAT) <3 x ULN; LDH < 2 x ULN
8. Creatinine clearance (Cockcroft-Gault) of >40 ml/min
9. Women of childbearing potential (WOCBP)* must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
10. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to the start of nivolumab
11. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception
12. CT-scan must be performed within 28 days prior to registration

Exclusion criteria 18

1. Signs of distant metastases on CT-scan and physical examination
2. Intercurrent illnesses, including but not limited to infections, unstable angina pectoris
3. Underlying medical conditions that, in the Investigator’s opinion, will make the administration of the study drug hazardous or obscure the interpretation of toxicity determination of adverse events
4. Positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
5. Active autoimmune disease or a documented history of autoimmune disease, or other medical conditions requiring systemic steroid or immunosuppressive medications, except for subjects with vitiligo, diabetes mellitus type 1, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis or resolved childhood asthma/atopy not requiring systemic treatment
6. Conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
7. Live vaccines in the 4 weeks prior to inclusion
8. History of uncontrolled medical or psychiatric illness
9. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
10. Current pregnancy or breastfeeding
11. Clinical obstruction
12. Clinical symptoms or radiological suspicion of perforation
13. Previous treatment with immune checkpoint inhibitors targeting including but not limited to CTLA-4, PD-1 or PD-L1
14. Previous treatment with chemotherapy
15. Radiotherapy prior to or planned post-surgery radiotherapy for disease under study
16. Active malignancies other than disease under study within 3 years prior to inclusion, except for malignancies with a negligible recurrence rate (e.g. <10% in 5 years)
17. History of allergy to study drug components
18. History of severe hypersensitivity reaction to any monoclonal antibody

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Efficacy as measured by major pathologic response rate (≤10% residual viable tumor (RVT))

Secondary endpoints 10

1. To assess the major pathological response rate (MPR, <10% viable tumor rest) and complete response rate and whether response correlates with DFS
2. To find biomarkers and evaluation strategies able to accurately assess complete and nearcomplete responses in order to pursue organ-sparing treatment (omission of surgery) in this patient population in future trials
3. To expand current exploratory translational analyses
4. Analysis of immune cell infiltration and the difference with inflamed pMMR tumors pre- and post-treatment: why is there no pathological response in pMMR tumors showing immune activation? And are there any differences between complete and near-complete responders?
5. Primary readout will be the effect of therapy on intratumoral T-cell infiltration, CD4, CD8 infiltration and immune checkpoints upregulation (including but not limited to PDL1 and LAG3 assessment for nivo/rela cohorts) in the time interval pre- and post-treatment in biopsies
6. Immunogenic mutational load will be determined by tumor tissue DNA WES. Peripheral blood DNA WES will also be performed and used as a control for somatic mutation sorting (only genes relating to colon cancer and/or immune-related genes, deemed informational for this study, will be assessed)
7. Immune suppressive pathways, IFN-y induced gene expression and COX2 induced gene expression changes will be analyzed by use of RNA sequencing on pre- and post-therapy tissue
8. Date of relapse, as determined by disease recurrence or disease-related death during follow-up after surgery. Follow-up will be performed according to local and/or national guidelines
9. Safety, evaluated by the incidence and severity of irAEs, SAEs and the frequency of delays of surgery >2 weeks from the intended date due to treatment related complications (if not a primary objective of the cohort)
10. To evaluate health-related quality of life through patient reported outcome measures

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Chalabi

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Chalabi

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 2 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications