Stage II patients with primary surgical treatment of cuMM are often at risk for recurrence of their disease. This risk may be reduced by adjuvant systemic treatment. Due to toxicities of adjuvant therapies the aim is to identify patients at high risk for relapse and to administer adjuvant treatment only to these patients. Thus an optimal balance between insufficient treatment vs. overtreatment has to be found.

To define these patients a prognostic biomarker test will be used in addition to conventional AJCC staging. AJCC staging takes into account several prognostic factors. However, to subdivide stage II melanoma patients into having a low or high risk for relapse further methods are needed.

This clinical trial will evaluate whether adjuvant nivolumab treatment will improve relapse-free survival (RFS) in patients with stage II high-risk melanoma as compared to observation only. The randomized approach of this trial offers the most objective method with the least influence of bias. Since patients with stage II melanoma are usually not receiving adjuvant treatment, no patient will be undertreated in case of randomization into observational arm.

The NivoMela trial is a randomized, controlled, prospective, multi-center national phase III trial with biomarker-based risk stratification.

Stage II melanoma patients having undergone surgery of the malignant melanoma will be screened using the MelaGenix GEP score to identify patients at high risk for relapse. It is expected, that 61% of screened patients will belong to this group.

Patients with a risk score of > 0.0 (HR 1.48, 1.11-1.98) corresponding to high risk of relapse will be randomized at a ratio of 2:1 to receive either nivolumab as adjuvant treatment (arm A) or observation only (arm B).

Stratification factors for randomization are:

1. Tumor stage: IIA versus IIB versus IIC
2. Gender: Female versus Male
3. Site of primary tumor: extremities versus trunk versus head &neck

All screened patients with a risk score of ≤ 0.0 who are not eligible for randomization will be followed for RFS, DMFS and OS for at least 5 years according to German Follow-up guidelines (Arm C).

Various factors that could potentially predict clinical response and incidence of AEs to treatment with nivolumab will be investigated in peripheral blood and tumor specimen taken at baseline. Data from these investigations will be evaluated for associations with clinical efficacy (eg, ORR, PFS, OS) and safety/toxicity (AE). The samples may also be used for exploratory analyses to assess biomarkers associated with melanoma and/or with immunotherapy treatment.

Inclusion Criteria:

1. Histologically confirmed diagnosis of stage II (AJCCv8) melanoma arising from a primary cutaneous site after surgery therapy

2. Sentinel node biopsy (SNB) without detection of melanoma deposits

3. Randomization not later than 12 weeks after SNB procedure

4. Tumor tissue from primary tumor must be provided for biomarker analyses. In order to be randomized, a subject must be classified by MelaGenix risk analysis.

5. Men and women at the age of 18 to 80 years

6. Signed written, informed consent

7. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study

8. Minimum life expectancy of five years excluding their melanoma diagnosis

9. ECOG performance status of 0-1

10. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization:

    • White blood cells (WBC) ≥ 2000/μL
    • Neutrophils ≥ 1500/μL
    • Platelets ≥ 100 x103/μL
    • Hemoglobin ≥ 9.0 g/dL
    • Serum creatinine ≤ 1.5xUL
    • Creatinine clearance (CrCl) ≥ 40mL/min (using the Cockcroft-Gault formula)
    • AST / ALT ≤ 3 x ULN
    • Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who may have total bilirubin < 3.0 mg/dL)

11. Negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) for women of childbearing potential (WOCBP) within 72 hours prior to registration.

    Women will be considered to be of childbearing potential unless surgically sterilized (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or being post-menopausal for at least 24 months or being amenorrheic for > 12 months and follicle-stimulating hormone (FSH) levels ≥ 40 IU/L.

12. WOCBP and male patients with partners of childbearing potential must agree to always use a highly effective form of contraception according to CTFG during the course of this study and for at least 5 months after last dose of study medication (in Arm A only).

Exclusion Criteria:

1. History of primary uveal or mucosal melanoma
2. No access to sufficient tumor tissue of primary tumor
3. SNB procedure > 12 weeks before randomization
4. Prior active malignancy within the previous 3 years except for locally curable cancers that have been apparently cured, such as: basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix, or breast. Exception: Participants with a history of non-ulcerated cutaneous/acral primary melanoma <1 mm in depth with no nodal involvement are allowed in this trial.
5. Prior or planned therapy with Interferon alpha, CTLA4 or PD-1 / PD L1 antibodies
6. Use of any investigational or non-registered product (drug or vaccine) other than the study treatment
7. Administration of live vaccines within 4 weeks before start of study therapy
8. Any immunosuppressive therapy given within the past 30 days
9. Active psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures
10. Active immune deficiencies or significant autoimmune disease
11. Serious cardiac, gastrointestinal, hepatic or pulmonary disease which would reduce life expectancy to less than five years
12. Serious intercurrent illness, requiring hospitalization
13. Other serious illnesses, e.g., serious infections requiring antibiotics or bleeding disorders
14. The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other active chronic infections (HBV, HCV) or has another confirmed or suspected immunosuppressive or immunodeficient condition
15. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, 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.
16. Hypersensitivity to the active substance or to any of the excipients
17. Participation in another clinical study within the 30 days before registration
18. For female patients: Pregnancy or breast-feeding
19. For WOCBP and male patients with partners of childbearing potential: Refusal or inability to use effective means of contraception
20. Lack of availability for clinical follow-up assessments
21. Legal incapacity or limited legal capacity