| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| stage 2-3 adenocarcinoma of the colon |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009957 |
| E.1.2 | Term | Colon carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective: To determine the safety and feasibility of pre-operative immunotherapy in colon cancer.
Additional Primary Objective for the expanded the MSI cohort: To assess efficacy of neoadjuvant ipilimumab plus nivolumab in terms of disease-free survival.
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|
| E.2.2 | Secondary objectives of the trial |
• To assess the major pathological response rate (MPR, <10% viable tumor rest) and complete response rate;
• To assess post-surgical outcome and infectious complications following neoadjuvant immunotherapy;
• To find biomarkers and evaluation strategies able to accurately assess complete and near-complete responses in order to pursue organ-sparing treatment (omission of surgery) in this patient population,
o Post-treatment CT-scans: can we use radiomics and/or artificial intelligence to accurately assess complete and near-complete response?
o Pre- and post-treatment PET-scans (possibly with novel tracers): is assessment of complete response rate more accurate with PET than CT-scans.
o ctDNA analysis: can we use ctDNA to assess complete response and is there a difference between complete and near-complete response in terms of minimal residual disease on ctDNA and risk of relapse?
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Signed written informed consent;
• Patients at least 18 years of age;
• Non-metastatic adenocarcinoma of the colon (and rectosigmoid considered as non-rectal and not undergoing neoadjuvant treatment)
o No signs of distant metastases on CT-scan and physical examination;
o dMMR cohorts 3+6: >cT3 and/or N+
• No clinical obstruction;
• No clinical symptoms or radiological suspicion of perforation;
• Colonoscopy must be performed after informed consent to obtain study-specific biopsies. If biopsies are not possible, patients cannot be included in the study;
• WHO performance status of 0 or 1;
• 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;
• Creatinine clearance (Cockcroft-Gault) of >40 ml/min;
• 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;
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab;
• 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;
• CT-scan must be performed within 28 days prior to registration;
• No previous treatment with immune checkpoint inhibitors targeting including but not limited to CTLA-4, PD-1 or PD-L1;
• No previous treatment with chemotherapy for colon cancer.
o For dMMR cohort no previous chemotherapy for any malignancies
• No radiotherapy prior to or planned post-surgery radiotherapy for disease under study;
• No 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);
• Allergies and Adverse Drug Reaction
o No history of allergy to study drug components
o No history of severe hypersensitivity reaction to any monoclonal antibody
• No intercurrent illnesses, including but not limited to infections, unstable angina pectoris;
• No 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;
• No positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection;
• No history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
• No 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;
• No 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;
• No live vaccines in the 4 weeks prior to inclusion;
• No history of uncontrolled medical or psychiatric illness;
• No psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
• No current pregnancy or breastfeeding.
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|
| E.4 | Principal exclusion criteria |
• Signed written informed consent;
• Patients at least 18 years of age;
• Non-metastatic adenocarcinoma of the colon (and rectosigmoid considered as non-rectal and not undergoing neoadjuvant treatment)
o No signs of distant metastases on CT-scan and physical examination;
o dMMR cohorts 3+6: >cT3 and/or N+
• No clinical obstruction;
• No clinical symptoms or radiological suspicion of perforation;
• Colonoscopy must be performed after informed consent to obtain study-specific biopsies. If biopsies are not possible, patients cannot be included in the study;
• WHO performance status of 0 or 1;
• 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;
• Creatinine clearance (Cockcroft-Gault) of >40 ml/min;
• 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;
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab;
• 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;
• CT-scan must be performed within 28 days prior to registration;
• No previous treatment with immune checkpoint inhibitors targeting including but not limited to CTLA-4, PD-1 or PD-L1;
• No previous treatment with chemotherapy for colon cancer.
o For dMMR cohort no previous chemotherapy for any malignancies
• No radiotherapy prior to or planned post-surgery radiotherapy for disease under study;
• No 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);
• Allergies and Adverse Drug Reaction
o No history of allergy to study drug components
o No history of severe hypersensitivity reaction to any monoclonal antibody
• No intercurrent illnesses, including but not limited to infections, unstable angina pectoris;
• No 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;
• No positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection;
• No history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
• No 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;
• No 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;
• No live vaccines in the 4 weeks prior to inclusion;
• No history of uncontrolled medical or psychiatric illness;
• No psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
• No current pregnancy or breastfeeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint for the MSS cohort: Safety will be measured by SAEs, SUSARS, and treatment related complications leading to delay in surgery (that according to the study timelines should be performed in week 5-6). Pre-operative treatment-related complications include all immune-related adverse events, attributable to the study medication, that lead to delay in surgery, with colitis being the most important, or delays due to the treatment of immunotherapy related toxicity. Logistical reasons or non-study-medication related complications (i.e. bacterial infections) leading to delay in surgery will not be considered dose-limiting toxicity. Post-operative complications including, but not limited to anastomotic dehiscence, wound dehiscence, abscess, perforation, bleeding and infection will be recorded. Feasibility will be measured by adherence to the timelines in the study protocol.
Analyses for efficacy and pathological response after immunotherapy in the MSS subgroup will be hypothesis-generating and will be used to guide future combinations or expansions within this study.
Primary endpoints for the DFS cohort: safety (proportion of patients receiving surgery on time) and disease-free survival defined as time since surgery until disease recurrence or death from any cause.
Additional Primary endpoint for the expanded MSI cohort: 3-year disease-free survival. A two-sided, one-sample logrank test calculated for a sample of 100 patients has 80% power at a 0.025 significance level (split alpha due to two primary endpoints) to detect a 3-year DFS of 93% if the 3-year DFS in the historic control group is (or synthetic matched control group) is 82%. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| This calculation assumes that patients will be accrued within 4.5 years and the data will be analyzed 6 months after accrual of the last patient. The 4.5 years accrual takes into account the 3-year accrual within the current NICHE trial that has already taken. |
|
| E.5.2 | Secondary end point(s) |
• To assess the major pathological response rate (MPR, <10% viable tumor rest) and complete response rate and whether response correlates with DFS;
• To find biomarkers and evaluation strategies able to accurately assess complete and near-complete responses in order to pursue organ-sparing treatment (omission of surgery) in this patient population in future trials:
o Post-treatment CT-scans: can we use radiomics to accurately assess complete and near-complete response?
o ctDNA analysis: can we use ctDNA to assess complete response and is there a difference between complete and near-complete response in terms of minimal residual disease on ctDNA and risk of relapse?
• To expand current exploratory translational analyses, in terms of;
o RNA sequencing and inflammatory signatures to find signatures predictive of response and possible escape mechanisms in non-responding tumors;
• 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?
• 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.
• 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).
• 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;
• 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;
Fresh tissue for the generation of organoids or the use for other analyses using tumor digest, will be collected whenever possible.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Pathology response: This calculation assumes that patients will be accrued within 4.5 years and the data will be analyzed 6 months after accrual of the last patient. The 4.5 years accrual takes into account the 3-year accrual within the current NICHE trial that has already taken.
Other secondary: various timepoints |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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