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 |
OpACIN-neo:
Primary objectives:
- 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 pathologic response rates at week 6 of the three neo-adjuvant combination schemes
PRADO extension cohort:
Primary objectives:
- To confirm the pathologic response rate (index lymph node, at week 6) of the winner neoadjuvant ipilimumab + nivolumab combination scheme identified in OpACIN-neo
- To show that patients with pathologic complete response (pCR) or pathologic near complete response (pnCR) in the index lymph node can be spared safely a CLND without affecting their prognosis
- To improve RFS at 24 months for patients achieving no pathologic response (pNR) by intensifying the subsequent adjuvant therapy
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E.2.2 | Secondary objectives of the trial |
OpACIN-neo:
- To describe relapse free survival
- To describe rate and type of late adverse events (up to 3 years)
- To determine immune activating capacity of the alternative combination schemes
PRADO extension cohort:
- To confirm radiologic response rate at week 6 of the winner neo-adjuvant combination scheme identified in OpACIN-neo
- To describe RFS and distant metastasis free survival (DMFS), for pCR, pnCR, pPR, and pNR patients at 2, 3 and 5 years
- To describe event free survival (EFS) for the total population
- To describe OS for the total population and for pCR/pnCR, pPR and pNR patients
- To describe the grade 3/4 immune related adverse event rate within the first 12 weeks
- To describe rate and type of late adverse events (up to 3 years)
- To determine differences in surgical morbidity for only marked index lymph node resection versus CLND
- To explore the immune activating capacity of the different response-driven treatment 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, i.e. methods with a failure rate of <1% per year when used consistently and correctly. 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
ipilimumab + 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
• 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 |
• Distantly metastasized melanoma
• Brain metastases
• 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 (except for non-responders in PRADO extension cohort;
in this group is adjuvant radiotherapy allowed)
• 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) |
OpACIN-neo
Primary endpoints:
- 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
- Pathologic response according to central revision (pathology of NKI).
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.
PRADO extension cohort:
Primary endpoints:
- Pathologic response rate according to central revision (by a pathologist of the NKI or MIA) of the marked index lymph node
- RFS at 24 months in patients achieving pCR or pnCR in their marked index lymph node and did not undergo CLND. RFS will be calculated from date of resection of the marked lymph node.
- RFS at 24 months in patients with pNR and being subsequently treated with adjuvant nivolumab plus optional radiotherapy (or dabrafenib/trametinib if BRAFV600E positive and treatment is approved). RFS will be calculated from day of resection of marked lymph node.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 weeks after start treatment for patihological response
24 months after lymph node resection for RFS |
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E.5.2 | Secondary end point(s) |
OpACIN-neo
Secondary endpoints:
- 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 surface marker expression (DSP) 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.
PRADO extension cohort:
Secondary endpoints:
- Response rate according to RECIST 1.1 at week 6
- RFS at 2, 3 and 5 years
- EFS at 2, 3 and 5 years
- DMFS at 2, 3 and 5 years
- OS at 2, 3 and 5 years
- Grade 3/4 immune-related adverse event rate according to CTCAE v4.03 within the first 12 weeks
- Surgical complication rates according to Clavien-Dindo surgical classification of only marked index lymph node resection vs. CLND
- 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 (e.g. T cell, TiS, and IFN), and surface marker expression (DSP) with tumor immune infiltrates and pathologic response
- Alteration in expansion/induction of tumor-resident TCR clones in peripheral blood from baseline to surgery at week.
- Quality of life as measured by EORTC QLQ C30 and the melanoma and the surgery subscale of FACT-M
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.8.1.1 | Randomised | No |
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 | Yes |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 10 |
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 |
Denmark |
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 | 7 |
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 | 9 |
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 | 14 |