Omitting Therapeutic Lymph Node Dissection in Patients with Melanoma (stage 3) and Major Pathological Response in the Index Lymph Node

Study Purpose

Rationale: The randomized trial NADINA has demonstrated that neoadjuvant treatment with nivolumab with ipilimumab improves event-free survival (EFS) in patients with macroscopic resectable stage III melanoma. In this study, therapeutic lymph node dissection (TLND) was standard of care, showing that patients achieving a major pathological response (MPR, i.e., ≤10% residual viable tumor bed) have an excellent outcome (EFS and Distant Metastasis Free Survival (DMFS)). The PRADO trial indicated that the MPR definition can also be revealed from a surrogate lymph node response, the index lymph node (ILN), allowing sparing the extensive surgery in MPR patients. In these MPR patients the DMFS was 100% after 1 year and 98% after 2 years, and recurrence-free survival (RFS) was 95% after 1 year and 93% after 2 years. Given that TLND is associated with morbidity and has a significant impact on health-related quality of life (HR-QoL) and healthcare costs, this study aims to prospectively investigate the safety of omitting TLND in patients who have an MPR within the ILN after neoadjuvant immunotherapy. Objectives: To investigate whether TLND can be safely omitted in patients with macroscopic resectable stage III (B/C/D) melanoma achieving an MPR within the ILN upon neoadjuvant treatment with immune checkpoint inhibitors (ipilimumab and nivolumab). Study design: This study is a prospective, single-arm phase 2 nationwide multicenter trial. Study population: Inclusion criteria for study participants are as follows:

- Patients must be eligible for neoadjuvant treatment.

- Patients must have a histologically confirmed diagnosis of macroscopic resectable stage III melanoma (stage III B/C/D) with one or more macroscopic lymph node metastasis.

- The patient must have a measurable tumor burden that qualifies (according to clinical practice) for neoadjuvant therapy.

Intervention: Omitting TLND in patients who achieve an MPR in the ILN following neoadjuvant ipilimumab and nivolumab. Main study endpoints: The two coprimary endpoints are 2-year Local Recurrence Free Survival (LRFS) and 2-year DMFS.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	16 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

- Patients must be eligible for neoadjuvant treatment (ipilimumab and nivolumab) - Patients must be 16 years of age or older.

- Patients must have a histologically confirmed diagnosis of macroscopic resectable stage III melanoma (stage III B/C/D) with one or more macroscopic lymph node metastase defined as either one: - a palpable node, confirmed as melanoma by pathology; a non-palpable but enlarged lymph node according to RECISTv1.1 (at least 15 mm in short axis), confirmed as melanoma by pathology; - a PET scan positive lymph node of any size confirmed as melanoma by pathology; - The patient must have a measurable tumor burden that qualifies (according to clinical practice) for neoadjuvant therapy with immune checkpoint inhibitors.

- Patients in whom ILN marking is feasible.

- Written informed consent.

Exclusion Criteria:

- Uveal/ocular or mucosal melanoma.

- WHO performance status of two or more.

- In-transit metastases only (without cytological or histological proven lymph node involvement) - Prior targeted therapy targeting BRAF and/or MEK for melanoma.

- Prior immunotherapy targeting CTLA-4, PD-1 or PD-L1 for melanoma.

- Patients with (history of) distant metastasis (stage IV melanoma)

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06754904
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	N/A
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	D.J. (Dirk) Grünhagen
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	N/A
Principal Investigator Affiliation	N/A
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Not yet recruiting
Countries
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Melanoma, Skin

Arms & Interventions

Arms

Experimental: Omitting TLND

Omitting TLND in patients who achieve an MPR in the ILN following neoadjuvant ipilimumab and nivolumab.

Interventions

Procedure: - Omitting TLND

Omitting TLND in patients who achieve an MPR in the index node following neoadjuvant ipilimumab and nivolumab.

Procedure: - Index node procedure

Index node procedure

Contact Information

This trial has no sites locations listed at this time. If you are interested in learning more, you can contact the trial's primary contact:

Drik Grünhagen, MD, PhD

[email protected]

+31 10 704 19 02

For additional contact information, you can also visit the trial on clinicaltrials.gov.

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