NADINA

Phase 3

Active, not recruiting

• Conditions: Stage III melanoma

• Registration Number: 2024-513519-28-00
• Lead Sponsor: Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Brief Summary

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

Detailed Description

Not available

Study Timeline

• Study First Posted: 2024-06-19
• Last Update Posted: 2025-03-09

Recruitment & Eligibility

• Status: Ongoing, recruitment ended
• Sex: Not specified
• Target Recruitment: 280

Inclusion Criteria

Men and women, at least 16 years of age

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 during and until 23 weeks post last ipilimumab + nivolumab infusion

Males who are sexually active with WOCP are not required to use contraception during treatment with nivolumab +/- ipilimumab, but 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 during and until 17 weeks post last dabrafenib + trametinib administration

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

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 lifeexpectancy 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;

Exclusion Criteria

Distantly metastasized melanoma;

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.

Women who are pregnant or breastfeeding;

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;

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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.		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.

Secondary Outcome Measures

Name	Time	Method
Pathologic response rate (categorized into pCR, near-pCR, MPR, pPR, pNR, according to INMC criteria70, see 7.1.1) in the neoadjuvant arm;		Pathologic response rate (categorized into pCR, near-pCR, MPR, pPR, pNR, according to INMC criteria70, see 7.1.1) in the neoadjuvant arm;
Correlation of pathologic response in the neoadjuvant arm to RFS, DMFS, and OS;		Correlation of pathologic response in the neoadjuvant arm to RFS, DMFS, and OS;
OS, defined as time between date of randomization and date of death from any cause;		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;		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;		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 (excluding melanoma in situ), melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, 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 (excluding melanoma in situ), melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, treatment-related death, or melanoma-related death, whichever occurs first;
Frequency and duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0;		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;		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;		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.		Performing health technology assessments comparing the neoadjuvant arm with the standard adjuvant arm.

Trial Locations

Locations (19)

Centre Leon Berard; 🇫🇷 Lyon, France

Assistance Publique Hopitaux De Paris; 🇫🇷 Boulogne-Billancourt, France

Institut Gustave Roussy; 🇫🇷 Villejuif, France

IRCCS Istituto Nazionale Tumori Fondazione Pascale; 🇮🇹 Naples, Italy

Maxima Medisch Centrum; 🇳🇱 Veldhoven, Netherlands

Amsterdam UMC Stichting; 🇳🇱 Amsterdam, Netherlands

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting; 🇳🇱 Amsterdam, Netherlands

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC); 🇳🇱 Rotterdam, Netherlands

Universitair Medisch Centrum Utrecht; 🇳🇱 Utrecht, Netherlands

Stichting Radboud universitair medisch centrum; 🇳🇱 Nijmegen, Netherlands

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Centre Leon Berard

🇫🇷Lyon, France

Mona Amini-Adle

Site contact

+33478785996

mona.amini-adle@lyon.unicancer.fr