iSCIB1+ in Combination With Ipilimumab and Nivolumab as First-Line Treatment for Advanced Unresectable Melanoma

This is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study evaluating the efficacy and safety of iSCIB1+ in combination with nivolumab and ipilimumab as first-line treatment for adults with advanced unresectable Stage III or Stage IV melanoma who express specific human leukocyte antigen (HLA) types.

Checkpoint inhibitor therapy has significantly improved outcomes for patients with advanced melanoma; however, many patients still experience disease progression. iSCIB1+ is a DNA-based therapeutic cancer vaccine designed to enhance immune recognition of melanoma-associated antigens and may improve the depth and durability of anti-tumor responses when used alongside checkpoint inhibition.

Approximately 550 participants will be randomized in a 1:1 ratio to receive either:

iSCIB1+ plus nivolumab and ipilimumab, or Placebo plus nivolumab and ipilimumab.

The primary objective is to determine whether the addition of iSCIB1+ improves progression-free survival (PFS) compared with placebo when both are administered in combination with nivolumab and ipilimumab.

Secondary objectives include evaluation of:

Overall survival (OS) Objective response rate (ORR) Duration of response (DoR) Disease control rate (DCR) Safety and tolerability Patient-reported quality of life outcomes

The study will also explore immune and biomarker responses in selected participants to better understand the relationship between vaccine-induced immune responses and clinical outcomes.

Participants will continue to be followed for disease progression, survival, safety, and other outcomes for up to four years after randomization.

5.1.Inclusion Criteria

• Participant has histologically confirmed, unresectable Stage III or Stage IV melanoma as defined by the AJCC (Gershenwald et al., 2017). Participants with a diagnosis of melanoma of unknown primary are eligible.
• Participant is positive for at least one of the following HLA alleles: HLA- with an HLA type of any one of HLA MHC class I: A2, A3, A31, Bw4, B44 and B35.
• Participant has been clinically evaluated, and checkpoint inhibition has been determined to be an appropriate treatment for their advanced disease.
• Participant's BRAF status must be known; participants with BRAF mutation positive disease may be enrolled without BRAF-inhibitor treatment at the discretion of the Study Investigator.
• Participant has at least one measurable lesion per RECIST 1.1 criteria by computed tomography CT scan or MRI.
• Participant is at least 18 years of age.
• Participant has a life expectancy of more than 6 months.
• Participant has an ECOG performance status of 0 or 1.
• Participant has adequate organ function as determined by the following laboratory values:

Absolute neutrophil count ≥ 1.5 x 109/L Lymphocyte count ≥0.5 x 109/L Platelet count ≥100 x 109/L Hemoglobin >9 g/dL (> 5.6 mmol/L) Serum creatinine or creatinine clearance ≤1.5x ULN >50 mL/min Serum total bilirubin ≤1.5 x ULN or <3.0 mg/dL if participant has Gilbert's syndrome Serum transaminases, AST and ALT ≤2.5 x ULN or ≤5.0 x ULN if liver metastases present

• Participant must be able and willing to provide written IRB/REC-approved informed consent prior to any study-related procedure.
• Women of childbearing potential must agree to use highly effective contraceptive methods prior to study entry, for the whole duration of study treatment, and for at least 5 months following the last dose or in accordance with the SmPC of the IC SOC CPI (whichever is most conservative).

See Appendix D: Guidance on Acceptable Contraceptive Methods for full guidance..

• Women of childbearing potential must have a negative serum pregnancy test at screening and within two days before IMP (or placebo) administration.
• Participant must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.

5.2.Exclusion Criteria

• Participant has a diagnosis of mucosal, ocular or acral melanoma.
• Participant has received prior systemic anti-PD1 treatment for advanced disease.
• Participant has received prior adjuvant treatment, defined as treatment following resection of all detectable disease, within 6 weeks of Day 1 (first dose of IMP).
• Participant has BRAF mutation positive disease with evidence of rapid PD.
• Participant has symptomatic brain metastases or carcinomatous meningitis. Symptomatic brain metastases are defined as brain metastases causing neurological signs or symptoms attributable to intracranial disease and/or requiring corticosteroid therapy for the management of brain metastasis-related symptoms. Participant is expected to require and elect any other form of systemic or localized anticancer therapy while receiving study treatment.
• Participants receive treatment with any investigational product within 28 days (or five half-lives of the treatment concerned if longer than 28 days) prior to Day 1.
• Participant has had a previous or current malignancy within 5 years, with the exception of melanoma and curatively treated local tumors.
• Participant has a concurrent illness/diagnosis which are uncontrolled and/or would preclude study conduct and assessment.
• Participant has NYHA class III or IV heart disease.
• Participant has a history of severe hypersensitivity reaction to treatment with a mAb.
• Participant has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents above physiological dosing.
• Received a live vaccine or non-live vaccine (including COVID-19 vaccines) within 7 days prior to first dose of study treatment.
• Participant has received systemic steroids or is receiving any other form of immune suppressant medication above physiological dosing within 7 days of Day 1.
• Participant is positive for HIV-1/2 infection or is positive for HBsAg or HCV antigen consistent with active infection.
• Participant has a known current or recent history (within the last year) of substance abuse including illicit drugs or alcohol to the extent where it would negatively affect compliance with the trial protocol based on Study Investigator's decision.
• Participant has received a solid organ transplant.
• Participant is breastfeeding during the study treatment phase, and for at least five months following the last dose or in accordance with the SmPC of I/N (whichever is most conservative).