E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic colorectal cancer |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
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 |
Parts 1, 1A and 1B (no EU subjects): - To characterize the safety and tolerability of combination therapies - To establish recommended dosing regimen for the combination (nivolumab plus ipilimumab plus trametinib OR nivolumab plus trametinib)
Part 2: To evaluate the Objective Response Rate (ORR) in all participants and subgroup of RAS mutation participants treated with nivolumab plus trametinib |
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E.2.2 | Secondary objectives of the trial |
Parts 1, 1A and 1B (no EU subjects): To evaluate preliminary efficacy
Part 2: - To evaluate efficacy in all participants treated with nivolumab and trametinib in comparison with regorafenib and TAS-102 - To characterize the safety and tolerability of combination therapies |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age ≥ 18, signed written informed consent • Histological or cytological confirmed diagnosis of previously treated mCRC with adenocarcinoma histology and in Stage IV per AJCC • Confirmed microsatellite status: only participants with pMMR/MSS mCRC are eligible • Verified KRAS, NRAS (extended RAS) and BRAF mutation status: BRAF V600 mutant are not eligible • Measurable disease per RECIST 1.1 • Provide Tumor Tissue sample at screening. • ECOG Performance Status of 0-1
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E.4 | Principal exclusion criteria |
1) Target Disease Exceptions a) Participants with BRAF V600 mutant colorectal cancer are NOT eligible for this study in Part 1, 1A, and 1B only. 2) Medical History and Concurrent Diseases a) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the participant to receive protocol therapy, or interfere with the interpretation of study results. b) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate/cervix/breast. c) Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. d) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. e) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents. f) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE [current version]) or baseline before administration of study drug. g) Toxicities from the prior anti-cancer treatment have not been resolved to Grade 1 (NCI CTCAE current version) at the time of study entry h) Current use of a prohibited medication. Treatment with botanical preparations (eg, herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to first dose of study treatment i) Prior treatment with any MEK inhibitor j) History of interstitial lung disease or pneumonitis. k) Inability to take oral medication or significant nausea and vomiting, malabsorption, external biliary shunt, significant bowel resection that would preclude adequate absorption of oral medication. l) Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule. m) Additional criteria for Part 2 only: i) Prior treatment with regorafenib or TAS-102 ii) Severe hepatic impairment (Child-Pugh C) iii) Any evidence of active bleeding, or hemorrhage or bleeding event ≥ NCI-CTCAE Grade 3 within 4 weeks prior to the start of study medication iv) Prior or current gastrointestinal perforation or fistula v) Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis, or pulmonary embolism within 6 months before the start of study medication vi) Non-healing wound, non-healing ulcer, or non-healing bone fracture vii) Active infection (ie, body temperature ≥ 38°C due to infection) 3) Physical and Laboratory Test Findings a) WBC < 2000/μL b) Neutrophils < 1500/μL c) Platelets < 100×103/μL d) Hemoglobin < 9.0 g/dL e) PT/INR and PTT > 1.5 ×ULN f) Serum creatinine > 1.5 ×ULN, unless creatinine clearance > 50 mL/min (measured or calculated using the Cockcroft-Gault formula) g) AST and/or ALT: > 3.0 ×ULN i) Part 2 ONLY: Participants with documented liver metastases with AST and ALT > 5.0 ×ULN will be excluded. h) Total bilirubin > 1.5 ×ULN i) Participants with Gilbert’s Syndrome who have a total bilirubin level of > 3.0 ×ULN will be excluded. i) Albumin < 3.0 g/dL j) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C antibody positive (except if HCV-RNA negative). k) History or evidence of cardiovascular risk n) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). o) Participants with serous retinopathy or retinal vein occlusion noted on ophthalmological evaluation, or participants with a history of serous retinopathy/retinal vein occlusion. 4) Allergies/Adverse Drug Reaction a) History of allergy/hypersensitivity to study drug components. b) History of severe hypersensitivity reaction to any monoclonal antibody. c) Have a known immediate or delayed hypersensitivity reaction/idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide. 5) Other Exclusion Criteria a) Prisoners/participants who are involuntarily incarcerated. b) Participants who are compulsorily detained for treatment of either a psychiatric or physical illness |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Under current accrual assumption, approximately 12 months from the FPFT. |
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E.5.2 | Secondary end point(s) |
BOR, DCR, DOR, TTR, and PFS by investigator, OS and Safety |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Under current accrual assumption, approximately 19 months from the FPFT. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
It is the first time that subjects will be admnistered Nivo/Tram and Nivo/Ipi/Tram together |
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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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 7 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
United States |
Belgium |
Germany |
Italy |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 12 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 29 |