E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage IV melanoma with no evidence of disease after surgery or radiotherapy |
Melanom im Stadium IV ohne Krankheitsanzeichen (No Evidence of Disease) nach kompletter chirurgischer Entfernung oder Strahlentherapie |
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E.1.1.1 | Medical condition in easily understood language |
Advanced melanoma with no evidence of disease after surgery or radiotherapy |
Fortgeschrittenes Melanom ohne Krankheitsanzeichen (No Evidence of Disease) nach Operation oder Bestrahlung |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025650 |
E.1.2 | Term | Malignant melanoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Ti assess the efficacy of adjuvant immunotherapy with Nivolumab alone or in combination with Ipilimumab in stage IV melanoma patients with no evidence of disease |
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E.2.2 | Secondary objectives of the trial |
Overall survival (OS) and safety / toxicity |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Despite major recent advances in melanoma biology and the immunology, these are still not completely understood, thus it appears mandatory to implement a comprehensive translational research program in order to establish the means to identify the group of patients most likely to benefit from therapy. The randomized design of the study will allow distinguishing predictive from prognostic biomarkers. This translational research program will focus on the discovery of predictive and/or surrogate biomarkers for a successful immune therapy of melanoma. Thus, sampling for biomarker studies (tumor tissue, plasma, serum) will be done as described in the study protocol. |
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E.3 | Principal inclusion criteria |
1.Stage IV melanoma arising from a primary cutaneous site or metastatic from an unknown primary site with no evidence of disease (NED) after surgery or radiation therapy (conducted within 8 weeks before enrolment) 2.Signed written informed consent 3.Men and women, aged 18 to 80 years 4.Known BRAF status 5.Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study 6.Minimum life expectancy of five years excluding their melanoma diagnosis 7.ECOG performance status of or 1 8.Tumor tissue from the resected site of disease must be provided for biomarker analyses. In order to be randomized a subject must have a PD-L 1 expression classification (positive (≥ 5% tumor cells expressing PD-L1) or negative (< 5% tumor cells expressing PD-L1)). If an insufficient amount of tumor tissue from the resected site is provided for analysis, acquisition of additional archived tumor tissue (block and/or slides) for the biomarker analyses is required. 9.Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration 10.Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization: oWBC ≥ 2000/μL oNeutrophils ≥ 1500/μL oPlatelets ≥ 100 x103/μL oHemoglobin ≥ 9.0 g/dL oSerum creatinine ≤ 1.5xUL oCreatinine clearance (CrCl) ≥ 40mL/min if using the Cockcroft-Gault formula 11.Negative pregnancy test for female subjects and effective contraception (Pearl-Index <1) for both male and female subjects if the risk of conception exists |
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E.4 | Principal exclusion criteria |
1.History of primary uveal or mucosal melanoma 2.Prior therapy with CTLA4 or PD1 antibodies 3.The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures. 4.Lack of availability for clinical follow-up assessments. 5.Any immunosuppressive therapy given within the past 30 days prior to study drug administration (excluding physiologic steroid hormone replacement) 6.Other malignancies within the past five years requiring treatment except basal or squamous skin carcinomas or carcinoma in situ of the cervix 7.Serious cardiac, gastrointestinal, hepatic or pulmonary disease reducing life expectancy to less than five years 8.Patients with serious intercurrent illness, requiring hospitalization. 9.Other serious illnesses, e.g., serious infections requiring antibiotics or bleeding disorders. 10.The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other chronic infections (HBV, HCV).or has another confirmed or suspected immunosuppressive or immunodeficient condition. 11.Known hypersensitivity reaction to any of the components of study treatment 12.Pregnancy (absence to be confirmed by ß-HCG serum test, minimum sensitivity 25IU/L or equivalent units of HCG)) or lactation period 13.Women of childbearing potential (WOCBP): Refusal or inability to use effective means of contraception (Pearl-Index <1). WOCBP receiving Nivolumab will be instructed to adhere to contraception until 31 weeks after the last dose of investigational product 14.Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year (Pearl-Index <1). Men receiving Nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception until 31 weeks after the last dose of investigational product 15.Known alcohol or drug abuse 16.Participation in another clinical study and use of any investigational or non-registered product (drug or vaccine) other than the study treatment within the 30 days before registration 17.Significant disease or condition which, in the investigator’s opinion, would exclude the patient from the study 18.Legal incapacity or limited legal capacity
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Study enrolment until day of progression/death |
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E.5.2 | Secondary end point(s) |
1. Overall survival (OS) 2. Safety/Toxicity |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Study enrolment until death/end of study |
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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 | 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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 |
Austria |
Germany |
Switzerland |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |