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.
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
