Combination Therapy With Nivolumab and PD-L1/IDO Peptide Vaccine to Patients With Metastatic Melanoma

Inclusion Criteria:

1. Age ≥ 18
2. The patient has unrespectable or metastatic melanoma with progressive, persistent or recurrent disease on or following treatment with standard of care agents
3. Patients belonging to one of the following patient groups will be enrolled:

   Cohort A: Anti PD-1/PD-L1 naïve patients (30 patients). The patient is a candidate for Nivolumab monotherapy. Prior anti-PD-1/anti-PD-L1 antibody treatment is not allowed.

   OR Cohort B: Extension cohort (10 patients). Progressive disease ON anti-PD-1 monotherapy.Subjects should not have experienced serious and/or life-threatening toxicity to antibody therapy.

   OR Cohort C: Extension cohort (10 patients). Progressive disease during follow up OFF anti-PD-1 after clinical benefit (SD/PR/CR) on anti-PD-1 therapy. Subjects should not have discontinued antibody therapy due to serious and/or lifethreatening toxicity
4. At least one measurable parameter according to RECIST 1.1.
5. The patient has an ECOG performance status of 0 or 1
6. The patient is a female of childbearing potential with negative pregnancy test
7. For women: Agreement to use contraceptive methods with a failure rate of \< 1 % per year during the treatment period and for at least 120 days after the treatment
8. For men: Agreement to use contraceptive measures and agreement to refrain from donating sperm
9. The patient has met the following hematological and biochemical criteria:

   1. AST and ALT ≤2,5 X ULN or ≤5 X ULN with liver metastases
   2. Serum total bilirubin ≤1,5 X ULN or direct bilirubin ≤ ULN for patient with total bilirubin level \> 1,5 ULN
   3. Serum creatinine ≤1,5 X ULN
   4. ANC (Absolute Neutrophil Count) ≥1,000/mcL
   5. Platelets ≥ 75,000 /mcL
   6. Hemoglobin ≥ 9 g/dL eller ≥ 5.6 mmol/L
10. Signed declaration of content after oral and written information about the protocol.

Exclusion Criteria:

1. The patient has not recovered to grade 0-1 from adverse events due to prior chemotherapy, radioactive or biological cancer therapy
2. The patient has not recovered from surgery or is less than 4 weeks from major surgery
3. The patient has a history of life-threatening or severe immune related adverse events on treatment with another immunotherapy and is considered to be at risk of not recovering
4. The patient is expected to require any other form of systemic antineoplastic therapy while receiving the treatment
5. The patient has a history of severe clinical autoimmune disease
6. The patient has a history of pneumonitis, organ transplant, human immunodeficiency virus positive, active hepatitis B or hepatitis C
7. The patient requires systemic steroids for management of immune-related adverse events experienced on another immunotherapy
8. The patient has active CNS metastases and/or carcinomatous meningitis. However, patients with subclinical brain metastases \< 1 cm can be included (maximum of 4 metastases \< 1 cm). (Patients with previously treated brain metastases may participate provided they are clinically stable. Patients with untreated brain metastasis will be excluded)
9. The patient has any condition that will interfere with patient compliance or safety (including but not limited to psychiatric or substance abuse disorders)
10. The patient is pregnant or breastfeeding
11. The patient is unable to voluntarily agree to participate by signed informed consent or assent
12. The patient has an active infection requiring systemic therapy
13. The patient has received a live virus vaccine within 30 days of planned start of therapy
14. Known side effects to Montanide ISA-51
15. Significant medical disorder according to investigator; e.g. severe asthma or chronic obstructive lung disease, dysregulated heart disease or dysregulated diabetes mellitus
16. Concurrent treatment with other experimental drugs
17. Any active autoimmune diseases e.g. autoimmune neutropenia, thrombocytopenia or hemolytic anemia, systemic lupus erythematosus, scleroderma, myasthenia gravis, autoimmune glomerulonephritis, autoimmune adrenal deficiency, autoimmune thyroiditis etc.
18. Severe allergy or anaphylactic reactions earlier in life