SCIB1 and iSCIB1+ in Melanoma Patients Receiving Nivolumab With Ipilimumab or SCIB1 With Pembrolizumab (The SCOPE Study)

Inclusion Criteria:

1. Histologically confirmed diagnosis of unresectable Stage III or Stage IV melanoma.

2. Not received prior systemic treatment for advanced disease. Prior neoadjuvant oradjuvant treatment, defined as treatment prior to or following resection of alldetectable disease, is permitted; last dose must be at least 24 weeks before thefirst dose of SCIB1 or iSCIB1+.

3. Checkpoint inhibition with either nivolumab with ipilimumab or pembrolizumab will bean appropriate treatment for their advanced disease.

4. BRAF status must be known; patients with BRAF mutation positive disease may beenrolled without BRAF inhibitor treatment at the discretion of the Investigator,provided that they have no evidence of rapidly progressing disease.

5. At least one measurable lesion per RECIST 1.1 criteria by CT scan or MRI.

6. Human leukocyte antigen (HLA)-A2 positive (applicable for cohort 1, 2 and 3).

7. Positive for HLA-DR4, HLA-DR7, HLA-DR53 or HLA-DQ6 (applicable for cohort 1, 2 and 3).

8. Patients for whom nivolumab with ipilimumab is determined to be an appropriatetreatment will be treated in cohort 4 with iSCIB1+ if:

9. the target HLA haplotype does not match as stated in criteria number 6 and 7,or

10. they are unable to wait for HLA screening results prior to enrolment orstarting treatment, or

11. cohort 1 and cohort 3 have completed or closed to recruitment.

12. At least 18 years of age.

13. A life expectancy of more than 3 months.

14. ECOG performance status of 0 or 1.

15. Adequate organ function as determined by protocol laboratory values.

16. Able and willing to provide written informed consent prior to any study relatedprocedure.

17. Women of child-bearing potential must have a negative serum pregnancy test duringscreening and be neither breastfeeding nor intending to become pregnant during studyparticipation, and shall be warned of potential foetal harm from nivolumab withipilimumab or pembrolizumab. Women of child-bearing potential must agree to usehighly effective contraceptive methods prior to study entry, for the whole durationof study treatment, and for 120 days after discontinuation of SCIB1 or iSCIB1+, ornivolumab with ipilimumab, or pembrolizumab, whichever is last.

18. Men who are potentially fertile with partners of childbearing potential must agreeto use highly effective contraceptive methods for the whole duration of studytreatment, and for 120 days after discontinuation of SCIB1 or iSCIB1+, or nivolumabwith ipilimumab, or pembrolizumab, whichever is last.

19. Must be willing and able to comply with scheduled visits, treatment plan, laboratorytests and other study procedures.

Exclusion Criteria:

1. A diagnosis of mucosal, acral or ocular melanoma.

2. Has central nervous system metastases or carcinomatous meningitis.

3. Has previously received a treatment to block cytotoxic T lymphocyte associatedprotein 4 (CTLA-4), programmed cell death protein 1 (PD-1), PD-L1, or programmeddeath-ligand 2 (PD-L2) with the following exception: patients who have receivedneoadjuvant or adjuvant treatment with these treatments are eligible, provided thatthe last dose was administered at least 24 weeks before the first dose of SCIB1 oriSCIB1+.

4. Patients with lactate dehydrogenase (LDH) > 2 x ULN.

5. Expected to require any other form of systemic or localized anticancer therapy whilereceiving study treatment.

6. Taking any systemic steroid therapy within 1 week of the first dose of study drug oris receiving any other form of immune suppressant medication. Physiological doses ofsystemic steroids such as those for the management of adrenal insufficiency, as wellas topical and inhaled steroids, such as those for the management of asthma, arepermitted.

7. Receiving treatment with any investigational product within 28 days (or 5 half-livesof the treatment concerned) prior to the first dose of study treatment.

8. Has a previous (within 5 years) or current malignancy with the exception ofmelanoma, and curatively treated local tumours.

9. Has a concurrent illness which would preclude study conduct and assessment.

10. Has New York Heart Association class III or IV heart disease, myocardial infarctionwithin previous 6 months, a heart rate of ≤ 50 beats per minute, a history ofsignificant cardiac abnormality and/or clinically significant abnormal baseline ECGreading, active ischemia, or any other uncontrolled cardiac condition.

11. Has a history of severe hypersensitivity reaction to treatment with a monoclonalantibody.

12. Has an active autoimmune disease or a documented history of autoimmune disease orsyndrome that requires systemic steroids or immunosuppressive agents (patients withvitiligo or resolved childhood asthma/atopy are an exception and are not excludedfor these conditions). The following patients are not excluded from the study:patients who require intermittent use of bronchodilators or local steroidinjections, patients with hypothyroidism stable on hormone replacement, and patientswho receive physiological doses of steroids as replacement therapy, such as thosefor the management of adrenal insufficiency. In such cases the recruitinginvestigator should discuss the patients' eligibility with the study Medical Monitorprior to enrolment.

13. Received a live vaccine within the 28 days prior to first dose of study treatment,or patient has received a non-live vaccine, including COVID-19 vaccines, within 14days prior to first dose of study treatment.

14. A known history of human immunodeficiency virus (HIV) or has any positive test forhepatitis B virus or hepatitis C virus indicating active acute or chronic infection.

15. A known current or recent history (within the last year) of substance abuseincluding illicit drugs or alcohol.