Comparing Intravenous or Intradermal Administration of Anti-CTLA-4 in Combination With Anti-PD1 Treatment in Patients With Melanoma

Prior treatment

• Prior treatment with CTLA-4 inhibitor or agonist, or anti-PD1, except for adjuvant nivolumab \> 6 months ago.
• Prior radiotherapy is permitted except on RECIST v1.1 target lesions within 2 weeks of start of trial treatment. Irradiated lesions without progression before start of treatment cannot be target lesions. Note: Patients must have recovered from all radiation-related toxicities, and not require corticosteroids.
• Active systemic infections requiring therapy, or signs or symptoms of a systemic infection within two weeks prior to baseline.
• Patient has used systemic corticosteroids to treat inflammatory or autoimmune symptoms within 15 days or other immunosuppressive drugs within 30 days prior to screening. Exceptions:
  • Patients that require intermittent use of inhalation or topical corticosteroids are eligible for the study.
  • Patient has received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) that, in the opinion of the Investigator, will not compromise protocol objectives.
• Patient has had treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor agents) within 2 weeks prior to baseline.
• Patient has had treatment with systemic immunostimulatory agents (including but not limited to interferons \[IFNs\] or interleukin-2 \[IL-2\]) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to baseline.
• Patient has had any major surgery within 4 weeks prior to enrolment or major surgery is scheduled during the study, with the exception of procedures that are part of the study site IIS.
• Currently participating in or has participated in a study of an investigational agent within 30 days of baseline or has not recovered from adverse events due to agents administered more than 4 weeks earlier, except A Phase 1a/1b, Multi-Centre, Open-Label, Dose-Escalation and Dose-Expansion Study in Patients with Solid Tumor Malignancies to Evaluate GEH200520 Injection / GEH200521 (18F) Injection Safety and Tolerability, Positron Emission Tomography Imaging, Pharmacokinetics, and Changes in Imaging after Treatment; NCT05629689, EU Trial number: 2024-515218-42-00.

Other illness

• History of another malignancy (that is progressing or requires active treatment) within the previous 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cancer that has undergone potentially curative therapy.
• Patient has a confirmed active SARS-CoV-2 infection.
• Patient has serious non-malignant disease or conditions that, in the opinion of the Investigator, could compromise patient safety or protocol objectives.
• Known history or evidence of immunodeficiency states (e.g., organ transplant, leukaemia, human immunodeficiency virus (HIV), hepatitis B, hepatitis C or known acquired immunodeficiency syndrome (AIDS)). NOTE: Testing for HIV must be performed at sites were mandated locally.
• Patient has history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanised antibodies or fusion proteins or known allergy to the study IMP ingredients and/or the proposed ICI therapy.
• Patient has a history of alcohol or drug abuse within the last year.

Lab values

• Patient has any safety laboratory test results (clinical chemistry, haematology, and urinalysis) that, in the opinion of the Investigator, could compromise patient safety or protocol objectives.
• Patient has any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of the ICI treatment, or that may affect the interpretation of the results or render the patient at high risk from complications.

Other

• Primary uveal or mucosal melanoma.
• Patient has 12-lead ECG significant findings during screening, per Investigator's as sessment.
• Patient has brain or bone-marrow metastasis that, in the opinion of the Investigator, could compromise patient safety or protocol objectives.
• Pregnancy or breastfeeding.
• For any reason, patient is considered by the local investigator to be an unsuitable candidate to participate in this study.

• Patient must be of age ≥ 18 years, and have a histologically confirmed diagnosis of locally advanced, surgically incurable, or metastatic cutaneous melanoma.
• European Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) performance status of 0 or 1.
• Patient must be eligible for anti-PD-1 treatment with nivolumab (group 1) or with ipilimumab + nivolumab (group 2) according to the treating physician.
• Patient must have one or more tumour lesions of which a biopsy can safely be obtained according to standard clinical practice.
• Patients must have a life expectancy of 3 months or greater.
• Patients must have measurable disease (according to RECIST v1.1) with at least one cutaneous metastasis. Note: measurable disease defined as: at least 1 visceral or nodal/soft tissue melanoma lesion that can be accurately and serially measured in at least 1 dimension and for which the longest diameter is ≥ 10 mm as measured by CT scan or MRI. Lymph nodes must measure ≥ 15 mm in their short axis to be considered measurable by CT-scan or MRI.
• Adequate bone marrow, hepatic, renal and coagulation function (to be conducted within 7 days prior to start therapy, during the baseline period):
  • Leukocyte count ≥ 3,5 × 109 / L
  • Platelets ≥ 100 × 109 / L.
  • Total bilirubin ≤ 3 × the upper limit of normal (ULN).
  • ASAT and ALAT ≤ 3.0 × ULN; except patients with documented liver metastases ASAT and/or ALAT ≤ 5.0 × ULN.
  • (Estimated) creatinine clearance ≥ 45 mL/min/1,73 m2.
  • Albumin ≥ 30g / L
  • LDH ≤ 2 x ULN
• Women of childbearing potential (WOCBP) must use contraception during the study and for 23 weeks after the last dose of nivolumab.
• Men who are sexually active with WOCBP must use contraception during the study plus 7 months after the last dose of nivolumab.
• Written and signed informed consent.