Removing only the main affected lymph node versus standard full lymph node removal for stage III melanoma
Randomized Controlled Trial of Selective Index Lymph Node Resection Versus Therapeutic Lymph Node Dissection After Neoadjuvant Immunotherapy for Stage IIIB-D Melanoma
This trial tests whether removing just the largest affected lymph node after six weeks of pre-surgery immunotherapy works as well as removing all lymph nodes in the area for people with stage III cutaneous melanoma in preventing recurrence over two years.
Quick facts
| Phase | Not applicable |
|---|---|
| Study type | Interventional |
| Enrollment | 1500 (estimated) |
| Ages | 18 Years and up |
| Sex | All |
| Sponsor | Melanoma Institute Australia Academic / other |
| Drugs / interventions | nivolumab, pembrolizumab, cemiplimab, ipilimumab, relatlimab, fianlimab, chemotherapy, immunotherapy, prednisone |
| Locations | 7 sites (Los Angeles, California and 6 other locations) |
| Trial ID | NCT07049276 on ClinicalTrials.gov |
What this trial studies
Participants receive six weeks of standard neoadjuvant immunotherapy and are then randomly assigned to either selective index lymph node resection (ILN) or the standard therapeutic lymph node dissection (TLND). The main goal is a non-inferiority comparison of 2-year recurrence-free survival between the two surgical approaches. Secondary endpoints include surgical complications (wound problems and lymphedema), quality of life, healthcare utilization, and pathological response in the removed nodes. The trial is multicenter, enrolling patients at specialist melanoma centers in Australia and at Cedars-Sinai in the United States.
Who should consider this trial
Good fit: Adults (≥18 years) with resectable pathological Stage IIIB, IIIC, or IIID cutaneous or unknown primary melanoma and at least one macroscopic lymph node confirmed by pathology are ideal candidates.
Not a fit: Patients with unresectable or more extensive nodal disease, contraindications to neoadjuvant immunotherapy, or who require full lymph node clearance for other clinical reasons are unlikely to benefit from the less extensive approach.
Why it matters
Potential benefit: If successful, patients could avoid a larger surgery and its complications while keeping the same chance of remaining cancer-free for two years.
How similar studies have performed: Recent neoadjuvant immunotherapy trials in melanoma have reported high rates of major pathological response (around 46–70%) and lower recurrence in responders, but randomized trials specifically comparing selective node resection to full dissection are relatively new.
Eligibility criteria
Show full inclusion / exclusion criteria
Inclusion Criteria:
1. Male or female patients ≥ 18 years of age at the time of consent
2. Written informed consent
3. Cytologically or histologically confirmed, resectable pathological Stage IIIB, C or D (Any T, N1b, N2b, N2c, N3b, or N3c) cutaneous or unknown primary melanoma, with or without primary tumour in situ
4. A minimum of one macroscopic lymph node, defined as:
* A palpable node, confirmed by pathology
* A non-palpable node, but enlarged per RECIST 1.1 criteria (≥ 15 mm in shortest diameter) and confirmed by pathology
* An ultrasound or PET/CT scan positive lymph node of any size, confirmed by pathology.
5. Up to 3 satellite (defined as any foci of clinically evident cutaneous and/or subcutaneous metastases occurring within 2 cm of but discontinuous from the primary melanoma) or in-transit metastases (defined as clinically evident cutaneous and/or subcutaneous metastases occurring \>2 cm from the primary melanoma in the region between the primary and the regional lymph node basin) are permitted if they are completely resectable.
6. Lymph node involvement in the groin (iliac, inguinal or both), axilla or neck only and may be unilateral or bilateral. Concurrent popliteal, epitrochlear or triangular intermuscular space (TIS) nodes permitted, as long as fully resectable.
7. Tumour amenable to a newly obtained core biopsy of a lesion which has not been previously irradiated. Archival tissue from a past primary or nodal lesion (if applicable) or tissue taken for current diagnosis will also be collected if available.
8. Systemic neoadjuvant immunotherapy is scheduled for administration with at least one PD-(L)-1 check point inhibitor (e.g. nivolumab, pembrolizumab, cemiplimab). The immunotherapy regimen may include other checkpoint inhibitors (e.g. ipilimumab, relatlimab, fianlimab). The patient should meet the fitness for treatment requirements as detailed in the relevant regulatory-approved Product Information or Summary of Product Characteristics.
9. Neoadjuvant course of treatment to be no longer than 6 weeks (allows for a maximum of 3 cycles at weeks 0, 3 and 6).
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
11. Anticipated life expectancy of \> 5 years.
Exclusion Criteria:
1. Uveal or mucosal melanoma.
2. Isolated satellite or in-transit metastases only (without any cytological or histological proven lymph node involvement).
3. Involvement of any lymph node basin other than groin, axilla or neck. Concurrent popliteal, epitrochlear or triangular intermuscular space (TIS) nodes permitted, as long as fully resectable.
4. Clinical or radiographic evidence of distant metastasis (any AJCC 8th ed M Stage).
5. Previous history of lymph node surgery to the same nodal basin, that was more extensive than a sentinel lymph node biopsy (SLNB).
6. Previous radiotherapy to the same nodal basin.
7. Any contraindication to the administration of nivolumab, ipilimumab, pembrolizumab or relatlimab per regulatory-approved product information and / or medical oncologist.
8. Prior anti-PD-1, CTLA-4, PDL-1 or LAG 3 antibody exposure, or an agent directed to another stimulatory or co-inhibitory T-cell receptor for any disease or any chemotherapy or experimental local or systemic drug treatment.
9. A plan to administer targeted therapy or any non-checkpoint inhibitor immunotherapy, or any intralesional therapy for melanoma in the neoadjuvant setting.
10. A plan to administer any experimental immunotherapy as part of a clinical trial in the neoadjuvant setting.
11. Known additional malignancies (unless adequately treated) active within the previous 3 years, except for locally curable cancers that have been apparently cured. The following malignancies, if undergone successful definitive resection or curative treatment, are permitted:
* Basal cell carcinoma of the skin
* Squamous cell carcinoma of the skin
* Carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ, but excluding carcinoma in situ of the bladder) that have undergone potentially curative therapy
* Prostatic intraepithelial neoplasia
* In situ melanoma
* Atypical melanocytic hyperplasia
* Stage I melanoma
* Other malignancies for which the patient has been disease free for 3 years, not requiring active anti-cancer therapy.
12. An active autoimmune disease or a requirement for chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study treatment. The following are permitted:
* Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc)
* Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if patient is on a stable dose
* Non-absorbed intra-articular steroid injections.
13. Has had an allogenic tissue/solid organ transplant.
14. Active Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
15. Has a known history of Human Immunodeficiency Virus (HIV). Note: no testing for HIV is required unless mandated by local health authority.
16. Pregnant or breastfeeding females.
17. Concurrent medical or social conditions that may prevent the patient from attending assessments or procedures per schedule.
Where this trial is running
Los Angeles, California and 6 other locations
- Cedars-Sinai Medical Centre — Los Angeles, California, United States (Not_yet_recruiting)
- Calvary Mater Newcastle — Newcastle, New South Wales, Australia (Recruiting)
- Melanoma Institute Australia — Wollstonecraft, New South Wales, Australia (Recruiting)
- Fiona Stanley Hospital — Murdoch, Western Australia, Australia (Not_yet_recruiting)
- Sunnybrook Health Sciences Centre — Toronto, Ontario, Canada (Not_yet_recruiting)
- San Maria della Misericordia Hospital — Perugia, Italy (Not_yet_recruiting)
- The Royal Marsden — London, United Kingdom (Not_yet_recruiting)
Study contacts
- Study coordinator: Alexander CJ van Akkooi
- Email: alexander.vanakkooi@melanoma.org.au
- Phone: +612 9911 7200
How to participate
- Review the eligibility criteria above with your treating physician.
- Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
- Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.