Evaluation of Tumor Microenvironment Alterations Following Intradermal Ipilimumab and Intravenous Nivolumab Combination Therapy in Patients with Unresectable Stage III-IV Melanoma

Trial ID: 2024-516545-39-01
Protocol: IpiD
Sponsor: Amsterdam UMC Stichting

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Diseases & Conditions

Malignant melanoma stage IV Malignant melanoma stage III

Objectives

The primary objective is to evaluate the systemic immunological effects of a single 20 mg dose of ipilimumab administered via intradermal injection in combination with intravenous nivolumab, compared to the systemic intravenous administration of both agents. This assessment is performed by measuring the frequency and functionality of tumor-specific T cells and regulatory T cells (Tregs) in peripheral blood. The secondary objective is to determine the clinical safety and tolerability of the local intradermal administration of ipilimumab in patients with unresectable stage III–IV melanoma eligible for first-line systemic nivolumab monotherapy.

Participants

The sponsor did not provide information regarding the total number of participants. The study population consists of male and female patients diagnosed with unresectable melanoma. Eligible participants must be aged 18 years or older and possess a histologically confirmed diagnosis of locally advanced, surgically incurable, or metastatic cutaneous melanoma. Required clinical characteristics include an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and measurable disease according to RECIST v1.1 with at least one cutaneous metastasis. Participants must demonstrate adequate bone marrow, hepatic, renal, and coagulation function. Additionally, women of childbearing potential and sexually active men are required to utilize contraception during the study and for a specified period following the final dose of nivolumab.

Plans and Procedures

This Phase 1b/2 study evaluates the systemic immunological effects in patients with unresectable stage III–IV melanoma. The research methodology compares the administration of a single 20 mg dose of ipilimumab via intradermal injection in combination with intravenous nivolumab against the systemic standard of care involving intravenous administration of both agents. The primary objective is to determine changes in the tumour microenvironment by assessing T cell subset frequencies and systemic activation within peripheral blood mononuclear cells. Secondary objectives include monitoring the safety of the intradermal administration through the reporting of adverse events. The trial is scheduled to take place between January 2026 and January 2028.

Treatment

The experimental treatment consists of ipilimumab, provided as a 5 mg/ml solution for infusion. In this study, a single 20 mg dose is administered via intradermal injection.

The control arm utilizes nivolumab as the standard of care, which is administered through intravenous infusion. This comparator group receives both ipilimumab and nivolumab via systemic intravenous administration.

Efficacy

Efficacy is evaluated through the assessment of T cell subset frequencies and systemic activation in peripheral blood mononuclear cells (PBMCs). The primary endpoints include the percentage of parent CD4+ and CD8+ T cells, alongside the evaluation of systemic activation defined by a 50% or greater increase in the expression of inducible T-cell costimulator (ICOS/CD278). These measurements are conducted at baseline and during on-treatment periods to compare the immunological effects of intradermal ipilimumab combined with intravenous nivolumab against systemic standard of care administration.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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 ipili-mumab + nivolumab (group 2) according to the treating physician.
Patient must be eligible for anti-PD-1 treatment with nivolumab (group 1) or with ipili-mumab + nivolumab (group 2) according to the treating physician.
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): o Leukocyte count ≥ 3,5 × 109 / L o Platelets ≥ 100 × 109 / L. o Total bilirubin ≤ 3 × the upper limit of normal (ULN). o Aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤ 3.0 × ULN; except patients with documented liver metastases ASAT and/or ALAT ≤ 5.0 × ULN. o (Estimated) creatinine clearance ≥ 45 mL/min/1,73 m2. o Albumin ≥ 30g / L o LDH ≤ 2 x ULN
Women of childbearing potential (WOCBP) must use contraception (see § 9.2.1) during the study and for 23 weeks after the last dose of nivolumab.
Men who are sexually active with WOCBP must use contraception (see § 9.2.1) during the study plus 7 months after the last dose of nivolumab.
Written and signed informed consent.

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Exclusion Criteria

Primary uveal or mucosal melanoma.
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.
Patient has 12-lead ECG significant findings during screening, per Investigator’s assessment.
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.
Patient has brain or bone-marrow metastasis that, in the opinion of the Investigator, could compromise patient safety or protocol objectives.
Active systemic infections requiring therapy, or signs or symptoms of a systemic infec-tion within two weeks prior to baseline.
Patient has used systemic corticosteroids to treat inflammatory or autoimmune symp-toms within 15 days or other immunosuppressive drugs within 30 days prior to screen-ing. Exceptions: o Patients that require intermittent use of inhalation or topical corticosteroids are eligible for the study. o Patient has received acute, low-dose, systemic immunosuppressant medica-tions (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.
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 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.
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.
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.
Pregnancy or breastfeeding.
Patient has a history of alcohol or drug abuse within the last year.
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 adminis-tered 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.
For any reason, patient is considered by the local investigator to be an unsuitable candidate to participate in this study.