Clinical trial NCT06754904: Omitting Therapeutic Lymph Node Dissection in Patients with Melanoma (stage 3) and Major Pathological Response in the Index Lymph Node
Official title: OMIT Trial: Omitting Therapeutic Lymph Node Dissection in Patients with Stage IIIB/C Melanoma and Major Pathological Response in the Index Lymph Node After Neoadjudvant Immunotherapy
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Melanoma, Skin
Keywords: Neoadjuvant
Ipilimumab
Nivolumab
Immunotherapy
Index node
Therapeutic lymph node dissection
Omitting
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
First posted: 2025-01-01
Enrollment: 213
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Omitting TLND in patients who achieve an MPR in the ILN following neoadjuvant ipilimumab and nivolumab.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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)

Primary outcomes:
measure: Local Recurrence Free Survival (LRFS)
timeFrame: 2 years after inclusion
measure: Distant Metastasis Free Survival (DMFS)
timeFrame: 2 years after inclusion
Secondary outcomes:
measure: Evaluation of health-related quality of life (HRQoL), EORTC QLQ C30
timeFrame: 3 years after inclusion
measure: Evaluation of health-related quality of life (HRQoL), FACT-M
timeFrame: 3 years after inclusion
measure: Description of the pathological response rates in the ILN
timeFrame: 1 year after inclusion
measure: Evaluation of the surgical morbidity, CTCAE v5
timeFrame: 2 year after inclusion
measure: Evaluation of the surgical morbidity, Clavien Dindo
timeFrame: 2 year after inclusion
measure: Radiological evaluation of the index lymph node
timeFrame: 1 year after inclusion
measure: Proportion of patients undergoing therapeutic lymph node dissection (TLND)
timeFrame: 5 years after inclusion
measure: Melanoma specific survival
timeFrame: 5 years after inclusion
measure: Overall survival
timeFrame: 5 years after inclusion
Other outcomes:
Locations:
Study officials:
References:
citation: Blank CU, Lucas MW, Scolyer RA, van de Wiel BA, Menzies AM, Lopez-Yurda M, Hoeijmakers LL, Saw RPM, Lijnsvelt JM, Maher NG, Pulleman SM, Gonzalez M, Torres Acosta A, van Houdt WJ, Lo SN, Kuijpers AMJ, Spillane A, Klop WMC, Pennington TE, Zuur CL, Shannon KF, Seinstra BA, Rawson RV, Haanen JBAG, Ch'ng S, Naipal KAT, Stretch J, van Thienen JV, Rtshiladze MA, Wilgenhof S, Kapoor R, Meerveld-Eggink A, Grijpink-Ongering LG, van Akkooi ACJ, Reijers ILM, Gyorki DE, Grunhagen DJ, Speetjens FM, Vliek SB, Placzke J, Spain L, Stassen RC, Amini-Adle M, Lebbe C, Faries MB, Robert C, Ascierto PA, van Rijn R, van den Berkmortel FWPJ, Piersma D, van der Westhuizen A, Vreugdenhil G, Aarts MJB, Stevense-den Boer MAM, Atkinson V, Khattak M, Andrews MC, van den Eertwegh AJM, Boers-Sonderen MJ, Hospers GAP, Carlino MS, de Groot JB, Kapiteijn E, Suijkerbuijk KPM, Rutkowski P, Sandhu S, van der Veldt AAM, Long GV. Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma. N Engl J Med. 2024 Nov 7;391(18):1696-1708. doi: 10.1056/NEJMoa2402604. Epub 2024 Jun 2.
citation: Reijers ILM, Menzies AM, van Akkooi ACJ, Versluis JM, van den Heuvel NMJ, Saw RPM, Pennington TE, Kapiteijn E, van der Veldt AAM, Suijkerbuijk KPM, Hospers GAP, Rozeman EA, Klop WMC, van Houdt WJ, Sikorska K, van der Hage JA, Grunhagen DJ, Wouters MW, Witkamp AJ, Zuur CL, Lijnsvelt JM, Torres Acosta A, Grijpink-Ongering LG, Gonzalez M, Jozwiak K, Bierman C, Shannon KF, Ch'ng S, Colebatch AJ, Spillane AJ, Haanen JBAG, Rawson RV, van de Wiel BA, van de Poll-Franse LV, Scolyer RA, Boekhout AH, Long GV, Blank CU. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial. Nat Med. 2022 Jun;28(6):1178-1188. doi: 10.1038/s41591-022-01851-x. Epub 2022 Jun 5.