E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with stage III melanoma |
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E.1.1.1 | Medical condition in easily understood language |
Patients with skin cancer that has spread to the lymph nodes. |
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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 | 10025670 |
E.1.2 | Term | Malignant melanoma stage III |
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 |
- To compare safety (immune related adverse events during the first 12 weeks) of three different neo-adjuvant combination schemes of ipilimumab + nivolumab - To compare radiological and pathological response rates at week 6 of the different neo-adjuvant combination schemes
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E.2.2 | Secondary objectives of the trial |
- To describe relapse free survival - To describe rate and type of late adverse events - To determine immune activating capacity of the alternative combination schemes
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Adults at least 18 years of age • World Health Organization (WHO) Performance Status 0 or 1 • Cytologically and histologically confirmed resectable stage III melanoma with one or more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can be biopsied, and no history of in-transit metastases within the last 6 months • No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years • Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse • No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1 • No immunosuppressive medications within 6 months prior study inclusion • Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN • Normal LDH • Women of childbearing potential (WOCBP) must use appropriate method(s) of contra-ception. 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
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E.4 | Principal exclusion criteria |
• Distantly metastasized melanoma • History of in-transit metastases within the last 6 months • No measurable lesion according to RECIST 1.1 • Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy • Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy • Radiotherapy prior or post-surgery • Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection • Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) • Allergies and Adverse Drug Reaction - History of allergy to study drug components - History of severe hypersensitivity reaction to any monoclonal antibody • Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events; • Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids; • Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion
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E.5 End points |
E.5.1 | Primary end point(s) |
- Safety as measured by the frequency of grade 3/4 immune-related adverse events (during the first 12 weeks). - Response rate according to RECIST 1.1 at week 6 - Pathological response according to central pathological revision (complete response, near complete response [only single tumor cells remaining], partial pathological response /micrometastasis, macroscopic disease) An interim analysis will be performed after 13 patients have been included in each arm (see 4.5), thus in total 39 patients have been included.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 weeks after start treatment |
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E.5.2 | Secondary end point(s) |
- Recurrence Free Survival. - Description of late adverse event (irAE, up to 3 years after treatment initiation, until new treatment) according to CTCAE v4.03 - Description of associations of mutational load, RNA tumor signatures, and tumor educated platelet signatures with tumor immune infiltrates and response
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
3 years after start treatment. |
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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 | 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 | 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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 |
Austria |
France |
Netherlands |
Sweden |
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 | 5 |
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 | 5 |
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 |