SWE-NEO: Swedish NeoAdjuvant Trial Comparing Monotherapy to Combined Immunotherapy in Resectable Stage III Melanoma

Phase 3

Not yet recruiting

• Conditions: Malignant Melanoma Stage III
• Interventions: Drug: Nivolumab; Drug: Nivolumab + Ipilimumab

• Registration Number: NCT06794775
• Lead Sponsor: Hildur Helgadottir

Brief Summary

At present two studies (SWOG S1801 and NADINA) have demonstrated superiority when using neoadjuvant treatment compared to adjuvant treatment only, but no studies have compared PD-1 monotherapy (SWOG 1801 regimen) to the PD-1/CTLA-4 combination (NADINA regimen) therapy. The SWE-NEO study aims to compare these two regimens, where the PD-1/CTLA-4 combination is potentially more effective, but also associated with more side effects.

Detailed Description

A phase III randomized controlled multicenter open-label trial. Patients will be randomized after a diagnosis of resectable stage III melanoma to have either two courses of CTLA-4 and PD-1 inhibitor combination therapy or PD-1 inhibitor monotherapy, before the pre-planned operation. In both arms, adjuvant treatment with a PD-1 inhibitor or with BRAF+MEK inhibitors in patients with a BRAF V600E mutation, will be given only to patients with no major pathological response in the operated tumor, with PD-1 inhibitor, or with BRAF+MEK inhibitors in patients with BRAF V600E mutation. Active follow-up will be performed for 3 years from surgery and followed for survival up until 10 years. Sequential blood and tumor samples will be collected for biomarker analyses.

Study Timeline

• Status Verified: 2025-01
• Study First Submitted: 2025-01-16
• Study First Submitted QC: 2025-01-22
• Study First Posted: 2025-01-27
• Last Update Submitted: 2025-01-28
• Last Update Posted: 2025-01-29
• Study Start: 2025-04-15
• Primary Completion: 2032-04-15
• Study Completion: 2032-04-15

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 128

Inclusion Criteria

1. Participants must be at least 18 years of age.

2. Can provide a signed informed consent as described in the protocol, including compliance with the requirements and restrictions listed in the ICF and in this protocol.

3. World Health Organization (WHO) Performance Status 0 or 1.

4. Patients must have

   1. Histologically or cytologically confirmed Stage III melanoma. In the case of in-transit metastases (with or without lymph node metastases)' ≤3 resectable in-transit metastases are allowed.
   2. Patients with cutaneous, acral, or unknown primary melanomas are eligible for enrollment.
   3. Resectable tumors are defined as having no significant vascular, neural or bony involvement. Only patients where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable.

5. Female patient of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

6. Female patients of childbearing potential must be willing to use a highly effective method of contraception, for the course of the study through 150 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Highly effective methods of contraception include one or more of the following:

   1. male partner who is sterile (vasectomised) prior to the female study subject's entry into the study and is the sole sexual partner for the female subject;
   2. hormonal (oral, intravaginal, transdermal, implantable or injectable)
   3. an intrauterine hormone-releasing system (IUS)
   4. an intrauterine device (IUD) with a documented failure rate of < 1%.

7. Male patients of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 150 days after the last dose of study therapy. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. A unique female sexual partner must postmenopausal, permanently sterilized (e.g. hysterectomy or tubal ligation), or use a highly effective method of contraception.

8. No other malignancies, except if treated with curative intent and with a cancer-related life expectancy of more than 5 years.

9. No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1.

10. No prior targeted therapy targeting BRAF and/or MEK.

Exclusion Criteria

1. Unresectable melanoma
2. Uveal/ocular or mucosal melanoma
3. Any serious or uncontrolled medical conditions that, in the investigator's opinion, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results .
4. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
5. Women who are pregnant or breastfeeding.
6. Any condition 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PD-1 inhibitor monotherapy	Nivolumab	Monotherapy with Nivolumab
PD-1/CTLA-4 inhibitor combination therapy	Nivolumab + Ipilimumab	Combination therapy with Nivolumab and Ipilimumab

Primary Outcome Measures

Name	Time	Method
Event-free survival (EFS)	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months	Event-free survival (EFS), defined as time from randomization to melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, or death from any cause (treatment-related, melanoma related or any other).

Secondary Outcome Measures

Name	Time	Method
Relapse-free survival (RFS)	From date of surgery until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months	Relapse-free survival (RFS), defined as time between date of surgery and date of melanoma recurrence, treatment-related death or melanoma-related death, whichever occurs first.
Distant metastasis-free survival (DMFS)	From date of randomization until the date of first documented distant metastasis or date of death from any cause, whichever came first, assessed up to 60 months	Distant metastasis-free survival (DMFS), defined as time between date of randomization and date of first distant metastasis, treatment-related death or melanoma-related death, whichever occurs first.
Overall survival (OS)	From date of randomization until the date of death from any cause, assessed up to 60 months	Overall survival (OS), defined as time between date of randomization and date of death.
Major pathological response (MPR)	Start of neoadjuvant therapy to end of neoadjuvant therapy, up to approximately two months	Major pathological response (MPR) (≤10% viable tumor cells), difference in MPR between combined ICI and monotherapy, central review of all surgical specimens by three expert melanoma pathologists.
Correlation of pathologic response to RFS, DMFS, and OS	From end of neoadjuvant therapy until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months	Correlation of pathologic response in each arm to RFS, DMFS, and OS.
Correlation of response to RFS, DMFS, and OS	From end of neoadjuvant therapy until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months	Correlation of radiological and clinical response evaluation to RFS, DMFS, and OS.
Proportion of patients having surgery according to plan	From start of neoadjuvant therapy to date of surgery, assessed up to 6 months	Number of patients having surgery according to plan (within 10 weeks from first neoadjuvant course).
Surgical complication rates	From surgery to date of any postoperative complication, assessed up to 3 months post surgery	Surgical complication rates according to Clavien-Dindo surgical classification.
Frequency of treatment-related adverse events (AEs)	From start of neoadjuvant therapy up to 1 year after last treatment	Frequency of all grade and grade 3-5 treatment-related adverse events (AEs) according to CTCAE 5.0.

Trial Locations

Locations (3)

Sahlgrenska University Hospital; 🇸🇪 Gothenburg, Sweden

Karolinska University Hospital; 🇸🇪 Stockholm, Sweden

Skane University Hospital; 🇸🇪 Lund, Sweden