Multicenter Phase 1b Trial Testing the Neoadjuvant Combination of Domatinostat, Nivolumab and Ipilimumab in IFN-gamma Signature-low and IFN-gamma Signature-high RECIST 1.1-measurable Stage III Cutaneous or Unknown Primary Melanoma

Inclusion Criteria:

* Adults at least 18 years of age.
* World Health Organization (WHO) Performance Status 0 or 1.
* Cytologically or histologically confirmed resectable stage III cutaneous melanoma (unknown primary also allowed) with one or more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can be biopsied, and no history of in-transit metastases within the last 6 months.
* No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years.
* Patient willing to undergo quadruple tumor biopsies and extra blood withdrawal during screening, week 3 and in case of relapse.
* The biopsies at screening should contain at least 30% tumor cells in order to get a reliable IFN-gamma signature
* No immunosuppressive medications within 6 months prior trial registration.
* Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN.
* Normal LDH.
* Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of ipilimumab + nivolumab.
* Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document.

Exclusion Criteria:

Distantly metastasized melanoma

* Uveal or mucosal melanoma.
* History of in-transit metastases within the last 6 months.
* No measurable lymph node lesion according to RECIST 1.1.
* Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy.
* Patients with any active gastrointestinal disorder that could interfere with the absorption of domatinostat (as per judgement of the investigator), such as ulcerative colitis, Crohn's disease, diabetic gastroparesis, or other syndromes characterized by malabsorption.
* Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy.
* Prior targeted therapy targeting BRAF and/or MEK.
* Prior radiotherapy.
* Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection; if treated and being at least one year free from HCV patients are allowed to participate.
* Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
* Allergies and Adverse Drug Reaction:

  * History of allergy to study drug components;
  * History of severe hypersensitivity reaction to any monoclonal antibody.
* Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events.
* Patients with a marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval \>450 msec (Grade 1 NCI-CTCAE); Long-QT-Syndrome) and patients receiving agents known to prolong the QT interval and known risk of Torsades de Pointes.
* Patients with significant current cardiovascular disease including:

  * Unstable angina pectoris within 6 months prior to screening
  * Uncontrolled hypertension
  * Congestive heart failure (New York Heart Association (NYHA) Class III or IV) related to primary cardiac disease
  * Conditions requiring anti-arrhythmic therapy (patients with status post pace maker implantation can be included)
  * Symptomatic ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry
* Women who are pregnant or lactating
* Use of other investigational drugs before study drug administration 30 days and 5 half-times before trial registration.