E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with stage III melanoma |
|
E.1.1.1 | Medical condition in easily understood language |
Patients with skin cancer that has spread to the lymph nodes. |
|
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 |
To compare the event-free survival (EFS) of neoadjuvant ipilimumab + nivolumab (followed by adjuvant nivolumab or dabrafenib + trametinib in patients not achieving a pathologic response) versus standard adjuvant nivolumab. |
|
E.2.2 | Secondary objectives of the trial |
Key secondary objective - To describe the Overall Survival (OS) in both arms;
Secondary objectives - To describe the RFS and distant metastases-free survival (DMFS) in both arms; - To describe the EFS including a new primary melanoma as an event in both arms; - To describe the (major) pathologic response rate in the neoadjuvant arm; - To evaluate the association between pathologic response and RFS, DMFS and OS, including analysis of the pathologic response subgroups (pCR, near pCR, pPR) and a subgroup analyses in BRAF wildtype and BRAFV600 mutated patients; - To describe the rate and type of immune-related adverse events; - To describe surgical morbidity; - To evaluate health-related quality of life (HRQoL) in both treatment arms; - To perform health technology assessments comparing the neoadjuvant arm with the standard adjuvant arm. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Men and women, at least 16 years of age; - World Health Organization (WHO) Performance Status 0 or 1; - Cytologically or histologically confirmed resectable stage III melanoma of cutaneous or unknown primary origin with one or more macroscopic lymph node metastases (clinical detectable), that can be biopsied and a maximum of 3 additional resectable in-transit metastases. A concurrent resectable primary melanoma is allowed. Clinical detectable lymph nodes are defined as either one: o a palpable node, confirmed as melanoma by pathology; o a non-palpable but enlarged lymph node according to RECISTv1.1 (at least 15 mm in short axis), confirmed as melanoma by pathology; o a PET scan positive lymph node of any size confirmed as melanoma by pathology; - No other malignancies, except adequately treated and with a cancer-related life-expectancy of more than 5 years; - No prior immunotherapy targeting CTLA-4, PD-1, PD-L1 or LAG-3; - No prior targeted therapy targeting BRAF and/or MEK; - No immunosuppressive medications within 6 months prior study inclusion (steroids equivalent to prednisolone ≤10 mg are allowed); - Screening laboratory values must meet the following criteria: WBC ≥2.0x109/L, neutrophils ≥1.5x109/L, platelets ≥100x109/L, hemoglobin ≥5.5 mmol/L, creatinine ≤1.5xupper limit of normal (ULN), AST ≤1.5x ULN, ALT ≤1.5x ULN, bilirubin ≤1.5x ULN (except for subjects with Gilbert syndrome who must have a total bilirubin <3.0 mg/dL); LDH level <1.5x ULN; - Women of childbearing potential (WOCP) must use appropriate method(s) of contraception, i.e. methods with a failure rate of <1% per year when used consistently and correctly, to avoid pregnancy for 23 weeks post last ipilimumab + nivolumab infusion; - Males who are sexually active with WOCP must use appropriate method(s) of contraception, i.e. methods with a failure rate of <1% per year when used consistently and correctly, to avoid pregnancy for 31 weeks post last ipilimumab + nivolumab infusion; - Patient willing and able to understand the protocol requirements and comply with the treatment schedule, scheduled visits, electronic patient outcome reporting, tumor biopsies and extra blood withdrawal during screening and in case of recurrence, and other requirements of the study; - Patient has signed the Informed Consent document. |
|
E.4 | Principal exclusion criteria |
- Distantly metastasized melanoma; - Uveal/ocular or mucosal melanoma; - in-transit metastases only (without cytological or histological proven lymph node involvement) - Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications. Subjects with resolved childhood asthma/atopy, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, are permitted to enroll; - Prior radiotherapy; targeting the affected lymph node region(s); - Subjects will be excluded if they test positive for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection. Subjects treated and being at least one year free from HCV are allowed to participate; - Subjects will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);Subjects with history of allergy to study drug components or history of severe hypersensitivity reaction to monoclonal antibodies. - Subjects with underlying medical conditions or active infection that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events; - Women who are pregnant or breastfeeding; - Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids >10 mg prednisolone daily equivalent; - Use of other investigational drugs before study drug administration 30 days or 5 half-times before study inclusion; - Psychological, familial, sociological, or geographical conditions that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
EFS, defined as time from randomization to melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, treatment-related death, or melanoma-related death, whichever occurs first. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 12 weeks, starting from week 12. |
|
E.5.2 | Secondary end point(s) |
Key secondary endpoint - OS, defined as time between date of randomization and date of death from any cause;
- RFS, defined as time between date of surgery and date of melanoma recurrence, treatment-related death or melanoma-related death, whichever occurs first; - DMFS, defined as time between date of randomization and date of first distant metastasis, treatment-related death or melanoma-related death, whichever occurs first; - EFS including new primary melanoma, defined as time from randomization to a new primary melanoma, melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, treatment-related death, or melanoma-related death, whichever occurs first; - Pathologic response rate (categorized into pCR, near-pCR, MPR, pPR, pNR, according to INMC criteria69, see 7.1.1) in the neoadjuvant arm; - Correlation of pathologic response in the neoadjuvant arm to RFS, DMFS, and OS; - Frequency and duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0; - Surgical complication rates according to Clavien-Dindo surgical classification; - Quality of life as measured by EORTC QLQ C30, the Melanoma Subscale and Melanoma Surgery Subscale of FACT-M, the Cancer Worry Scale, HADS questionnaire, EQ-5D-5L, the immunotherapy-specific questionnaire, an assessment of work performance, sexual health, and Amsterdam Cognition Scan; - Performing health technology assessments comparing the neoadjuvant arm with the standard adjuvant arm.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Every 12 weeks, starting from week 12. Adverse events are monitored continuously. Questionairs: At baseline, week 6 week 12, and every 12 weeks until week 60, then then at month 18, 24, 30, and 36. Continously ePRO collection using KAIKU app. |
|
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 2 |
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 | 14 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
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 |
United States |
France |
Italy |
Poland |
|
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
|
|
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 | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |