E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Resectable stage III melanoma patients with one or more measurable lymph node metastases that can be biopsied, no history of in-transit metastases within the last 6 months, naïve for CTLA-4/PD-1/PD-L1 immunotherapy. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with melanoma, which has only spread to the lymph glands (stage III melanoma) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 |
The purpose of this study is to test the safety of three different combinations of nivolumab and ipilimumab before surgery in patients with stage III melanoma (skin cancer) which has spread to the lymph nodes.
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 look at whether nivolumab and ipilimumab can prevent the tumour from coming back, and what effect the drug has on the immune system.
In addition to the study into how well these treatments work, we also want to find out how the body responds to the treatment. This is done by taking blood samples and samples of the tumour tissue.
- 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 |
1. Adults at least 18 years of age
2. World Health Organization (WHO) Performance Status 0 or 1
3.Cytologically or 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
4. No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years
5. Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse
6. No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1
7. No immunosuppressive medications within 6 months prior study inclusion
8. 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
9. Normal LDH
10. 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
11. 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 ipilimumab + nivolumab
12. 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
13. Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception
14. Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document. |
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E.4 | Principal exclusion criteria |
1. Distantly metastasized melanoma
2. History of in-transit metastases within the last 6 months
3. No measurable lesion according to RECIST 1.1
4. 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
5. Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy
6. Radiotherapy prior or post-surgery
7. 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
8. Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
9. Allergies and Adverse Drug Reaction History of allergy to study drug components History of severe hypersensitivity reaction to any monoclonal antibody
10. 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;
11. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
12. Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion
13. Pregnant or nursing |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measurements in this trial will be toxicity, radiologic, and pathologic response rate in the three arms, and only in case of inconclusive results, we will analyze the broadening of the melanoma neo-antigen-specific T cell responses. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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
An interim analysis will be performed after 13 patients have been included in each arm |
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E.5.2 | Secondary end point(s) |
- Recurrence Free Survival (RFS) - Description of late adverse event (up to 3 years after treatment initiation) 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 - Alteration in magnitude or breadth of the neo-antigen specific T cell responses in peripheral blood from baseline to surgery at week 6 in each 10 randomly chosen patients per arm. |
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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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 6 |
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 | 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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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 | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 29 |