Efficacy and Safety of Nintedanib Combined With Paclitaxel Chemotherapy for Patients With BRAF wt Metastatic Melanoma

Inclusion Criteria: 1. Histologically confirmed, (surgically incurable or unresectable) stage III or IV, BRAF V600 wildtype metastatic cutaneous malignant melanoma. 2. Written informed consent 3. A minimum of 1 measurable lesion according to RECIST v1.1 criteria. 4. ECOG of 0-1. 5. Adequate hematologic, renal and liver function within 14 days prior to initiation of dosing: * Hematologic: * Absolute neutrophil count (ANC) ≥1.5 x 109/L * Hemoglobin ≥ 9 g/dL (5.6 mmol/L; Subjects may not have had a transfusion within 7 days of screening assessment) * Platelets: ≥ 100 x 109/L * Hepatic * Total bilirubin: ≤ 1.0 x ULN * AST and ALT: ≤ 1.5 x ULN (In the case of liver metastases: 2.5 x ULN) * Renal o Serum creatinine: ≤ 1.5 mg/dL (133 µmol/L) or, if greater than 1.5 mg/dL: Calculated creatinine clearance: ≥ 50 mL/min 6. effective method of contraception for at least 3 months after completion of nintedanib/placebo monotherapy as directed by their physician. 7. Men should use an effective method of contraception during treatment and for at least 6 months after completion of paclitaxel treatment and for at least 3 months after completion of nintedanib/placebo monotherapy as directed by their physician. 8. Patients must have recovered from all prior treatment-related toxicities to NCI CTCAE (v4.0) Grade of 0 or 1, except for toxicities not considered a safety risk such as alopecia. 9. Male or female, aged 18 years or older 10. Life expectancy at least 3 months Exclusion Criteria: 1. Prior systemic therapy with taxanes or kinase inhibitors. Any prior therapy for metastatic disease must have been discontinued at least 4 weeks prior to initiation of dosing. 2. Major surgery or radiation therapy within 4 weeks of starting the study treatment (minor surgical procedures such as biopsies are allowed, however patients must have recovered). 3. Known inherited predisposition to bleeding or thrombosis and therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid \< 325mg per day) Patients with the following coagulation parameters will be excluded: * International normalised ratio (INR) \> 2 * Prothrombin time (PT) and partial thromboplastin time (PTT): \> 50% of deviation of institutional ULN 4. History of clinically significant haemorrhagic or thromboembolic event in the past 6 months 5. NCI CTCAE (V4.0) grade 3 hemorrhage within 4 weeks of starting the study treatment. 6. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization. 7. Serious, non-healing wound, ulcer, or bone fracture. 8. Known CNS disease: * Previous Grade 2 or higher sensory neuropathy. * History of or known spinal cord compression, or carcinomatous meningitis, or evidence of active brain metastases (e.g. stable for \<4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before randomization) or leptomeningeal disease on screening CT or MRI scan. 9. Any of the following within the 6 months prior to enrolment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism. 10. New York Heart Association (NYHA) Grade II or greater congestive heart failure. 11. Ongoing cardiac dysrhythmias of NCI CTCAE Version 4.0 grade ≥ 2. 12. Inadequately controlled hypertension (defined as systolic blood pressure \> 150 and/or diastolic blood pressure \> 100 mmHg on antihypertensive medications). 13. Symptomatic peripheral vascular disease. 14. Proteinuria at screening as demonstrated by urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible). 15. Known hypersensitivity reaction to any of the components of study treatment (e.g. contrast media) or other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study. 16. Previous cancer (unless a RFS interval of at least 5 years) with the exception of surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin. 17. Known clinically uncontrolled infectious disease including HIV positivity or AIDS-related illness and active or chronic hepatitis C and/or B infection. 18. Pregnancy (absence to be confirmed by ß-hCG test) or lactation period. 19. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule 20. Active alcohol or drug abuse 21. Treatment with other investigational drugs or treatments in another clinical trial within the past four weeks before start of therapy or concomitantly with this trial. 22. Legal incapacity or limited legal capacity 23. Significant weight loss (\> 10% of body weight) within past 6 months prior to inclusion into the trial