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Adjuvant Nivolumab Treatment in Stage II (IIA, IIB, IIC) High-risk Melanoma



Juli 2020

Letztes Update:


Indikation (Clinical Trials):


Erwachsene (18+)

Phase 3

University Hospital, Essen



Dirk Schadendorf, Prof. Dr.
Principal Investigator
University Hospital, Essen


Dirk Schadendorf, Prof. Dr.
Phone: +49 (0) 201 / 723-2431
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Universitätsklinikum Würzburg - Klinik für Dermatologie, Venerologie und Allergologie
97080 Würzburg
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Bastian Schilling, Prof. Dr.
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Universitätsmedizin Rostock -Klinik und Poliklinik für Dermatologie und Venerologie
18057 Rostock
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Julia Katharina Tietze, Dr. med.
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St. Josef-Hospital - Dermatologische Studienambulanz
44791 Bochum
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Thilo Gambichler, Prof. Dr.
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Universitätsklinik Carl Gustav Carus der Technischen Universität Dresden - Klinik und Poliklinik für Dermatologie
01307 Dresden
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Friedegund Meier, Prof. Dr.
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University Hospital Essen, Department of Dermatology, Skin Cancer Center
45122 Essen
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Dirk Schadendorf, Prof. Dr.
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Universitätsklinikum Freiburg - Klinik für Dermatologie und Venerologie
79106 Freiburg
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Frank Meiß, Dr. med.
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Universitätsklinikum Gießen und Marburg GmbH - Klinik für Dermatologie und Allergologie
35392 Gießen
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Daniela Göppner, PD Dr. med.
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Universitätsklinikum Hamburg-Eppendorf - Hauttumorzentrum
20246 Hamburg
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Christoffer Gebhardt, Prof. Dr.
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Universitätsklinikum Schleswig-Holstein, Campus Kiel - Dermatologie
24105 Kiel
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Axel Hauschild, Prof. Dr.
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Universitätsklinikum Leipzig - Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie
04103 Leipzig
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Jan C. Simon, Prof. Dr.
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Universitätsklinikum Mannheim - Klinik f. Dermatologie, Venerologie u. Allergologie
68167 Mannheim
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Jochen S. Utikal, Prof. Dr.
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Klinikum der Universität München - Klinik und Poliklinik für Dermatologie und Allergologie
80337 München
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Max Schlaak, PD Dr.
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Universitätsklinikum Münster - Zentrale Studienkoordination für innovative Dermatologie (ZID)
48149 Münster
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Carsten Weishaupt, Dr. med.
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Fachklinik Hornheide - Internistische Onkologie
48157 Münster
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Michael Fluck, Dr. med.
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Harzklinikum Dorothea Christiane Erxleben - Klinik für Dermatologie & Allergologie
06484 Quedlinburg
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Jens Ulrich, Prof. Dr.
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Universitätsklinikum Tübingen - Dermatoonkologie
72076 Tübingen
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Thomas K Eigentler, Prof. Dr.
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Detailed Description:

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



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


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


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


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


Primary outcome:

1. Relapse-Free Survival (RFS) rates (Time Frame - 5 years):
Determination of efficacy of nivolumab in a biomarker-selected high-risk-enriched stage II melanoma patient population in comparison to control receiving observation only in a 2 (Arm A=nivolumab) : 1 (Arm B=observation) randomization, as measured by Relapse-Free Survival (RFS) rates at 36 and 60 months. RFS is defined as the time from date of registration until documented tumor progression date or date of death of any cause, whichever occurs first in all patients tested with the MelaGenix gene expression profiling (GEP).

Secondary outcome:

1. Distant metastasis-free survival (DMFS) rates (Time Frame - 5 years):
DMFS rates at 36 and 60 months

2. Melanoma-specific survival (MSS) rates (Time Frame - 5 years):
MSS rates at 36 and 60 months

3. Overall survival (OS) rates (Time Frame - 5 years):
OS rates at 36 and 60 months

4. Adverse events ≥ Grade 3 according to CTCAE Version 5.0 criteria (Safety / Toxicity) (Time Frame - Arm A: Until 100 days after discontinuation of dosing of the investigational product; Arm B: Until 1 year after patient´s written consent):
All adverse events ≥ Grade 3 according to CTCAE Version 5.0 criteria, that are definitely, probably, or possibly related to the administration of the investigational agent

5. Clinical utility/decision impact of the MelaGenix Gene Expression Profiling (GEP) Score in stratifying patients for adjuvant therapy (Time Frame - 5 years):
Patients with a risk score of > 0.0 (HR 1.48, 1.11-1.98) will be classified as high risk for relapse. It is expected, that 61% of screened patients will belong to this group. Patients with a risk score of score of ≤ 0.0 will be classified as low risk for relapse.


  • Experimental: Nivolumab (Arm A)
    Patients with a risk score of > 0.0 corresponding to high risk of relapse (randomized): Nivolumab will be applied at a flat dose of 480 mg given as 60-minute iv infusion every 4 weeks for 12 doses over 1 year. Afterwards these patients will receive intense clinical follow up according German Follow up guidelines.
  • No Intervention: Observation, High Risk (Arm B)
    Patients with a risk score of > 0.0 corresponding to high risk of relapse (randomized): Control group (observation only). These patients will receive intense clinical follow up but no further specific therapy according German Follow up guidelines.
  • No Intervention: Observation, Low Risk (Arm C)
    Patients with a risk score of ≤ 0.0 corresponding to low risk of relapse who are not eligible for randomization: These patients will receive intense clinical follow up but no further specific therapy according German Follow up guidelines. Documentation of clinical outcome of these patients.

Geprüfte Regime

  • Nivolumab (Opdivo):
    480 mg nivolumab fixed dose given as 60-minute iv infusion every 4 weeks for 12 doses over 1 year


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