Melanoma (Skin Cancer)Phase 1/2IpiDNCT07615881
Comparing Intravenous or Intradermal Administration of Anti-CTLA-4 in Combination With Anti-PD1 Treatment in Patients With Melanoma
A Phase 1/2 study testing Group 1 - Intradermal ipilimumab and Group 2 - Conventional treatment in people with Melanoma (Skin Cancer), run by Amsterdam UMC, location VUmc.
Trial summary
This study investigates whether a single intradermal (i.d.) injection of low-dose anti-CTLA-4 (ipilimumab), given at the tumour site, can enhance immune activation when combined with standard intravenous (i.v.) anti-PD-1 therapy in patients with advanced melanoma. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma (Skin Cancer)
- What is being tested?
- Group 1 - Intradermal ipilimumab and Group 2 - Conventional treatment
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- No sites listed yet
- Study dates
- Jul 2026to Jul 2029
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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 as sessment.
- 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.
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- 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 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.
- 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 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.
- For any reason, patient is considered by the local investigator to be an unsuitable candidate to participate in this study.
About this study
Official title: Changes in the Tumour Microenvironment After Intravenous or Intradermal Administration of Anti-CTLA-4 in Combination With Anti-PD1 Treatment in Patients With Melanoma
This study investigates whether a single intradermal (i.d.) injection of low-dose anti-CTLA-4 (ipilimumab), given at the tumour site, can enhance immune activation when combined with standard intravenous (i.v.) anti-PD-1 therapy in patients with advanced melanoma. While combined checkpoint inhibition is effective, it is associated with high toxicity, creating a need for strategies that maintain efficacy with fewer side effects.
Preclinical and early clinical data suggest that local (intradermal) CTLA-4 blockade can stimulate systemic anti-tumour immune responses with reduced toxicity, potentially by reactivating suppressed T cells in tumour-draining lymph nodes. This study compares systemic immune effects of intradermal versus standard intravenous CTLA-4 administration, both combined with nivolumab.
The primary objective is to assess systemic immune activation by measuring changes in CD4+ and CD8+ T-cell frequencies and ICOS expression in peripheral blood. Additional immune monitoring includes blood sampling, tumour biopsies, and advanced imaging using FDG-PET/CT and a novel CD8-targeted PET tracer. The study is a prospective, open-label pilot trial in patients with metastatic melanoma, with follow-up for clinical outcomes and immune response over approximately 13 weeks.
Read the detailed description
Rationale Immune checkpoint inhibitors (ICI) represent a drastic breakthrough in the treatment of meta static melanoma. Inhibitors of the PD-1 immune checkpoint (e.g., nivolumab and pembroli zumab), when given as monotherapy, are more effective than monotherapy with CTLA-4 checkpoint inhibitors (e.g., ipilimumab), with objective response rates of 30 - 40 %. The com bination of anti-PD-1/anti-CTLA-4 has shown to increase the response rate up to 58 % with a median survival of 72 months (1). However, this also leads to significant increased rates of toxicity (59 % grade 3 or higher adverse events versus 22 % for nivolumab monotherapy) (2). Thus, there is a need to identify effective treatments with less side effects. In clinical stage II melanoma, intradermal (i.d.) administration of low, 20 mg dose anti-CTLA-4 tremelimumab at the primary tumour excision site has shown promising immune-modulatory effects in a previ ous trial (3). Effects were seen both in the draining sentinel lymph node and systemically with out any serious toxicity as seen with systemic therapy. We assume that the increased systemic rates of tumour antigen-specific T cells observed is due to "re-awakening" of previously primed, but immune suppressed T cells in the primary tumour-draining lymph nodes. Based on these interesting results it is hypothesized that the clinical response to monotherapy anti-PD-1 could be improved, even in more advanced stages, by combining with a low dose of i.d. anti-CTLA 4 delivered to the primary tumour-draining lymph basin.
Systemic effects of blockage of CTLA4 can be effectively measured by increase of expression of ICOS on different immune subsets (4). Indeed, the systemic changes after i.d. injection of anti-CTLA-4 in the previous study by van de Pul et al. resulted in dose-dependent increases in ICOS expression on CD4+/CD8+ cells in all patients (> 200% change in the highest dose cohort of 20 mg tremelimumab at 3 weeks), and prolonged decrease in activated Tregs and myeloid derived suppressor cells (MDSCs) in all dose cohorts starting already after one week(3). As patients in the IpiD study will have more advanced disease, we hypothesize that systemic CTLA4 blockage effects will lead to at least 50% increase in ICOS expression CD4+/CD8+ cells from baseline to on treatment. Changes in the immune response upon treat ment can be monitored locally in tumour biopsies, which are cumbersome and thus less at tractive for repeat assessments. Systemic effects can also be evaluated in peripheral blood mononuclear cells (PBMCs) as described above, or with molecular imaging. The latter has the advantage to provide whole body, localised information of biological processes related to the mechanism of action as well as tumour responses. For example, in melanoma patients treated with ipilimumab monotherapy, an early Fluorine-18 Fluorodeoxyglucose ([18F]FDG) PET/CT scan can predict outcome after two cycles for treatment with melanoma (5), and baseline spleen-to-liver ratio of [18F]FDG uptake was associated with poor outcome(6, 7). However, [18F]FDG is a generic tracer to visualise metabolic activity and as such will not discriminate between tumour cells and immune cells. Novel tracers focussing on immune effector cells, like the CD8+ T cell tracers (among others GEH200520/GEH200521 (18F)), can be of added value here to study the systemic effect of i.d. anti CTLA-4. This study protocol therefore will combined with the accompanying CD8 T cell imaging protocol (NCT05629689; EU Trial number: 2024 515218-42-00).
Primary objective To determine the systemic immunological effects of a single dose of 20 mg ipilimumab locally administered i.d. in combination with i.v. standard of care nivolumab or systemic standard of care i.v. administration of ipilimumab and nivolumab as determined with the frequency and functionality of CD4+/CD8+ T cells in peripheral blood cells.
Main trial endpoints T cell subset frequencies (as percentage of parent) and , and systemic activation (determined as a 50 % or greater increase in expression of ICOS/CD278 (inducible T-cell costimulatory) in PBMCs CD4+ and CD8+ T cells from baseline to on-treatment in both groups. We hypothesize a ≥ 50% increase in ICOS expression in at least 8 out of 12 patients.
Trial design Prospective monocentre open-label, pilot clinical trial. Patients included in this pilot study will also be included in an imaging study with a novel [18F]CD8 tracer (A Phase 1a/1b, Multi-Centre, Open-Label, Dose-Escalation and Dose-Expansion Study in Patients with Solid Tumour Ma lignancies to Evaluate GEH200520 Injection / GEH200521 (18F) Injection Safety and Tolera bility, Positron Emission Tomography Imaging, Pharmacokinetics, and Changes in Imaging after Treatment; NCT05629689, EU Trial number: 2024-515218-42-00). Trial duration for safety is expected to be 13 weeks (92 days), follow up for survival will be collected during standard of care.
Trial population Group 1: Adult patients with advanced/metastatic melanoma with (a) tumour lesion(s) that can be biop sied, who are eligible according to standard of care for first-line systemic treatment with i.v. nivolumab. 2.7.2 Group 2 Adult patients with advanced/metastatic melanoma with (a) tumour lesion(s) that can be biop sied, who are eligible according to standard of care for first-line systemic treatment with i.v. nivolumab.
Group 2: Adult patients with advanced/metastatic melanoma with (a) tumour lesion(s) that can be biop sied, who are eligible according to standard of care for first-line systemic treatment with i.v. ipilimumab and nivolumab.
Interventions Group 1: Patients will be treated once by local i.d. injection of 20 mg ipilimumab around (the excision site of the) primary tumour or around a skin metastasis, in combination with i.v. nivolumab according to standard of care (continuous)
Group 2: Patients will be treated according to standard of care with i.v. ipilimumab (4 cycles) combined with i.v. nivolumab (continuous).
For all patients, nivolumab will be continued until complete response (iCR), confirmed progres sive disease (iCPD) or intolerance of treatment according to standard clinical practice. After 24 weeks, it is allowed to stop anti-PD1 treatment in case of a confirmed partial remission (iPR), according to standard practice or the Safe-Stop study protocol (NCT05652673), which evaluates the safety and efficacy of early discontinuation after 24 weeks in patients with a favourable response. This approach is consistent with emerging clinical practice (8-10). Pa tients will have regular follow up according to standard clinical practice, including radiological evaluation (RECIST v1.1 and iRECIST with CT and/or MRI imaging: 1st evaluation at 3 months, follow-up evaluations every 3 months in case of SD and every 4 months in case of PR/CR until disease progression/death or stop treatment due to progression of disease/toxicity).
If not already performed as part of standard of care staging, all patients will undergo a [18F]FDG PET/CT according to EARL criteria before start of treatment, and a tumour biopsy at baseline and on treatment. Blood samples (total volume 150 mL) will be collected at in total 5 timepoints (at baseline, and 1 week, 3 weeks, 32 days, and 12 weeks after start of treatment).
All patients will participate in: 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.
REFERENCES
- Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022;40(2):127-37. 2. Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.
Lancet Oncol. 2018;19(11):1480-92. 3. van Pul KM, Notohardjo JCL, Fransen MF, Koster BD, Stam AGM, Chondronasiou D, et al. Local delivery of low-dose anti-CTLA-4 to the melanoma lymphatic basin leads to systemic T(reg) reduction and effector T cell activation. Sci Immunol. 2022;7(73):eabn8097.
- Fu T, He Q, Sharma P. The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res. 2011;71(16):5445-54. 5. Kudura K, Dimitriou F, Basler L, Forster R, Mihic-Probst D, Kutzker T, et al. Prediction of Early Response to Immune Checkpoint Inhibition Using FDG-PET/CT in Melanoma Patients. Cancers (Basel). 2021;13(15). 6. Sachpekidis C, Anwar H, Winkler J, Kopp-Schneider A, Larribere L, Haberkorn U, et al. The role of interim (18)F-FDG PET/CT in prediction of response to ipilimumab treatment in metastatic melanoma. Eur J Nucl Med Mol Imaging. 2018;45(8):1289-96. 7. Wong A, Callahan J, Keyaerts M, Neyns B, Mangana J, Aberle S, et al. (18)F-FDG PET/CT based spleen to liver ratio associates with clinical outcome to ipilimumab in patients with metastatic melanoma. Cancer Imaging. 2020;20(1):36.
- Conditions
- Melanoma (Skin Cancer)
- Being tested
- Group 1 - Intradermal ipilimumab, Group 2 - Conventional treatment
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Group 1 - Intradermal ipilimumabDrug
Patients will be treated once by local i.d. injection of 20 mg ipilimumab around (the excision site of the) primary tumour or around a skin metastasis, in combination with i.v. nivolumab according to standard of care (continuous).
Group 2 - Conventional treatmentDrug
Patients will be treated according to standard of care with i.v. ipilimumab (4 cycles) combined with i.v. nivolumab (continuous).
| Study group | Role | What they receive |
|---|---|---|
| Group 1 - Intradermal ipilimumab | Experimental | Patients with advanced/metastatic melanoma who are eligible for standard of care i.v nivolumab will be treated by a single local i.d. injection of 20 mg ipilimumab around (the exci sion site of the) primary tumour or around a skin metastasis, in combination with treatment with i.v. nivolumab continuous. Receives: Drug: Group 1 - Intradermal ipilimumab |
| Group 2 - Conventional treatment | Active comparator | Patients with advanced advanced/metastatic melanoma who are eligible for standard for standard of care i.v. ipilimumab (4 cycles) combined with i.v. nivolumab (continuous) will be treated accordingly. Receives: Drug: Group 2 - Conventional treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Immunological effects
To determine the systemic immunological effects of standard i.v nivolumab combined with a single dose of 20 mg ipilimumab locally administered i.d. or systemic i.v. administration of standard of care dose ipilimumab as determined with the frequency and functionality of CD4+ and CD8+ T cells in peripheral blood cells.
Measured: 13 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 May 2026
- Study startJul 2026 (estimated)
- Primary completionJul 2028 (estimated)
- Study completionJul 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Melanoma (Skin Cancer)Studies of the same condition, open and under way.
- More trials run by Amsterdam UMC, location VUmcThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 18 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Amsterdam UMC, location VUmc
- Sponsor type
- University, hospital or other
- Collaborators
- GE Healthcare
- Responsible party
- Principal investigator, C. Menke- van der Houven van Oordt, Amsterdam UMC, location VUmc
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07615881
- Sponsor's protocol ID
- 2026.0392
- Other IDs
- 2024-516545-39-00
- Acronym
- IpiD
- Status last verified
- May 2026
- First submitted
- 22 May 2026
- Last updated
- 29 May 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Changes in the Tumour Microenvironment After Intravenous or Intradermal Administration of Anti-CTLA-4 in Combination With Anti-PD1 Treatment in Patients With Melanoma
- ClinicalTrials.gov ID
- NCT07615881
- Acronym / sponsor ID
- IpiD / 2026.0392
- Conditions
- Melanoma (Skin Cancer)
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 18 participants (estimated)
- Lead sponsor
- Amsterdam UMC, location VUmcUniversity, hospital or other
- Collaborators
- GE Healthcare
- Study start
- Jul 2026 (estimated)
- Primary completion
- Jul 2028 (estimated)
- Study completion
- Jul 2029 (estimated)
- First posted
- 29 May 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study investigates whether a single intradermal (i.d.) injection of low-dose anti-CTLA-4 (ipilimumab), given at the tumour site, can enhance immune activation when combined with standard intravenous (i.v.) anti-PD-1 therapy in patients with advanced melanoma. While combined checkpoint inhibition is effective, it is associated with high toxicity, creating a need for strategies that maintain efficacy with fewer side effects.
Preclinical and early clinical data suggest that local (intradermal) CTLA-4 blockade can stimulate systemic anti-tumour immune responses with reduced toxicity, potentially by reactivating suppressed T cells in tumour-draining lymph nodes. This study compares systemic immune effects of intradermal versus standard intravenous CTLA-4 administration, both combined with nivolumab.
The primary objective is to assess systemic immune activation by measuring changes in CD4+ and CD8+ T-cell frequencies and ICOS expression in peripheral blood. Additional immune monitoring includes blood sampling, tumour biopsies, and advanced imaging using FDG-PET/CT and a novel CD8-targeted PET tracer. The study is a prospective, open-label pilot trial in patients with metastatic melanoma, with follow-up for clinical outcomes and immune response over approximately 13 weeks.
Detailed description
Rationale Immune checkpoint inhibitors (ICI) represent a drastic breakthrough in the treatment of meta static melanoma. Inhibitors of the PD-1 immune checkpoint (e.g., nivolumab and pembroli zumab), when given as monotherapy, are more effective than monotherapy with CTLA-4 checkpoint inhibitors (e.g., ipilimumab), with objective response rates of 30 - 40 %. The com bination of anti-PD-1/anti-CTLA-4 has shown to increase the response rate up to 58 % with a median survival of 72 months (1). However, this also leads to significant increased rates of toxicity (59 % grade 3 or higher adverse events versus 22 % for nivolumab monotherapy) (2). Thus, there is a need to identify effective treatments with less side effects. In clinical stage II melanoma, intradermal (i.d.) administration of low, 20 mg dose anti-CTLA-4 tremelimumab at the primary tumour excision site has shown promising immune-modulatory effects in a previ ous trial (3). Effects were seen both in the draining sentinel lymph node and systemically with out any serious toxicity as seen with systemic therapy. We assume that the increased systemic rates of tumour antigen-specific T cells observed is due to "re-awakening" of previously primed, but immune suppressed T cells in the primary tumour-draining lymph nodes. Based on these interesting results it is hypothesized that the clinical response to monotherapy anti-PD-1 could be improved, even in more advanced stages, by combining with a low dose of i.d. anti-CTLA 4 delivered to the primary tumour-draining lymph basin.
Systemic effects of blockage of CTLA4 can be effectively measured by increase of expression of ICOS on different immune subsets (4). Indeed, the systemic changes after i.d. injection of anti-CTLA-4 in the previous study by van de Pul et al. resulted in dose-dependent increases in ICOS expression on CD4+/CD8+ cells in all patients (> 200% change in the highest dose cohort of 20 mg tremelimumab at 3 weeks), and prolonged decrease in activated Tregs and myeloid derived suppressor cells (MDSCs) in all dose cohorts starting already after one week(3). As patients in the IpiD study will have more advanced disease, we hypothesize that systemic CTLA4 blockage effects will lead to at least 50% increase in ICOS expression CD4+/CD8+ cells from baseline to on treatment. Changes in the immune response upon treat ment can be monitored locally in tumour biopsies, which are cumbersome and thus less at tractive for repeat assessments. Systemic effects can also be evaluated in peripheral blood mononuclear cells (PBMCs) as described above, or with molecular imaging. The latter has the advantage to provide whole body, localised information of biological processes related to the mechanism of action as well as tumour responses. For example, in melanoma patients treated with ipilimumab monotherapy, an early Fluorine-18 Fluorodeoxyglucose ([18F]FDG) PET/CT scan can predict outcome after two cycles for treatment with melanoma (5), and baseline spleen-to-liver ratio of [18F]FDG uptake was associated with poor outcome(6, 7). However, [18F]FDG is a generic tracer to visualise metabolic activity and as such will not discriminate between tumour cells and immune cells. Novel tracers focussing on immune effector cells, like the CD8+ T cell tracers (among others GEH200520/GEH200521 (18F)), can be of added value here to study the systemic effect of i.d. anti CTLA-4. This study protocol therefore will combined with the accompanying CD8 T cell imaging protocol (NCT05629689; EU Trial number: 2024 515218-42-00).
Primary objective To determine the systemic immunological effects of a single dose of 20 mg ipilimumab locally administered i.d. in combination with i.v. standard of care nivolumab or systemic standard of care i.v. administration of ipilimumab and nivolumab as determined with the frequency and functionality of CD4+/CD8+ T cells in peripheral blood cells.
Main trial endpoints T cell subset frequencies (as percentage of parent) and , and systemic activation (determined as a 50 % or greater increase in expression of ICOS/CD278 (inducible T-cell costimulatory) in PBMCs CD4+ and CD8+ T cells from baseline to on-treatment in both groups. We hypothesize a ≥ 50% increase in ICOS expression in at least 8 out of 12 patients.
Trial design Prospective monocentre open-label, pilot clinical trial. Patients included in this pilot study will also be included in an imaging study with a novel [18F]CD8 tracer (A Phase 1a/1b, Multi-Centre, Open-Label, Dose-Escalation and Dose-Expansion Study in Patients with Solid Tumour Ma lignancies to Evaluate GEH200520 Injection / GEH200521 (18F) Injection Safety and Tolera bility, Positron Emission Tomography Imaging, Pharmacokinetics, and Changes in Imaging after Treatment; NCT05629689, EU Trial number: 2024-515218-42-00). Trial duration for safety is expected to be 13 weeks (92 days), follow up for survival will be collected during standard of care.
Trial population Group 1: Adult patients with advanced/metastatic melanoma with (a) tumour lesion(s) that can be biop sied, who are eligible according to standard of care for first-line systemic treatment with i.v. nivolumab. 2.7.2 Group 2 Adult patients with advanced/metastatic melanoma with (a) tumour lesion(s) that can be biop sied, who are eligible according to standard of care for first-line systemic treatment with i.v. nivolumab.
Group 2: Adult patients with advanced/metastatic melanoma with (a) tumour lesion(s) that can be biop sied, who are eligible according to standard of care for first-line systemic treatment with i.v. ipilimumab and nivolumab.
Interventions Group 1: Patients will be treated once by local i.d. injection of 20 mg ipilimumab around (the excision site of the) primary tumour or around a skin metastasis, in combination with i.v. nivolumab according to standard of care (continuous)
Group 2: Patients will be treated according to standard of care with i.v. ipilimumab (4 cycles) combined with i.v. nivolumab (continuous).
For all patients, nivolumab will be continued until complete response (iCR), confirmed progres sive disease (iCPD) or intolerance of treatment according to standard clinical practice. After 24 weeks, it is allowed to stop anti-PD1 treatment in case of a confirmed partial remission (iPR), according to standard practice or the Safe-Stop study protocol (NCT05652673), which evaluates the safety and efficacy of early discontinuation after 24 weeks in patients with a favourable response. This approach is consistent with emerging clinical practice (8-10). Pa tients will have regular follow up according to standard clinical practice, including radiological evaluation (RECIST v1.1 and iRECIST with CT and/or MRI imaging: 1st evaluation at 3 months, follow-up evaluations every 3 months in case of SD and every 4 months in case of PR/CR until disease progression/death or stop treatment due to progression of disease/toxicity).
If not already performed as part of standard of care staging, all patients will undergo a [18F]FDG PET/CT according to EARL criteria before start of treatment, and a tumour biopsy at baseline and on treatment. Blood samples (total volume 150 mL) will be collected at in total 5 timepoints (at baseline, and 1 week, 3 weeks, 32 days, and 12 weeks after start of treatment).
All patients will participate in: 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.
REFERENCES
- Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022;40(2):127-37. 2. Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.
Lancet Oncol. 2018;19(11):1480-92. 3. van Pul KM, Notohardjo JCL, Fransen MF, Koster BD, Stam AGM, Chondronasiou D, et al. Local delivery of low-dose anti-CTLA-4 to the melanoma lymphatic basin leads to systemic T(reg) reduction and effector T cell activation. Sci Immunol. 2022;7(73):eabn8097.
- Fu T, He Q, Sharma P. The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res. 2011;71(16):5445-54. 5. Kudura K, Dimitriou F, Basler L, Forster R, Mihic-Probst D, Kutzker T, et al. Prediction of Early Response to Immune Checkpoint Inhibition Using FDG-PET/CT in Melanoma Patients. Cancers (Basel). 2021;13(15). 6. Sachpekidis C, Anwar H, Winkler J, Kopp-Schneider A, Larribere L, Haberkorn U, et al. The role of interim (18)F-FDG PET/CT in prediction of response to ipilimumab treatment in metastatic melanoma. Eur J Nucl Med Mol Imaging. 2018;45(8):1289-96. 7. Wong A, Callahan J, Keyaerts M, Neyns B, Mangana J, Aberle S, et al. (18)F-FDG PET/CT based spleen to liver ratio associates with clinical outcome to ipilimumab in patients with metastatic melanoma. Cancer Imaging. 2020;20(1):36.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group 1 - Intradermal ipilimumab | Experimental | Drug: Group 1 - Intradermal ipilimumabPatients with advanced/metastatic melanoma who are eligible for standard of care i.v nivolumab will be treated by a single local i.d. injection of 20 mg ipilimumab around (the exci sion site of the) primary tumour or around a skin metastasis, in combination with treatment with i.v. nivolumab continuous. |
| Group 2 - Conventional treatment | Active comparator | Drug: Group 2 - Conventional treatmentPatients with advanced advanced/metastatic melanoma who are eligible for standard for standard of care i.v. ipilimumab (4 cycles) combined with i.v. nivolumab (continuous) will be treated accordingly. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- 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.
Key exclusion criteria (23 listed)
- 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 as sessment.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Group 1 - Intradermal ipilimumabPatients will be treated once by local i.d. injection of 20 mg ipilimumab around (the excision site of the) primary tumour or around a skin metastasis, in combination with i.v. nivolumab according to standard of care (continuous). | Drug | Group 1 - Intradermal ipilimumab |
| Group 2 - Conventional treatmentPatients will be treated according to standard of care with i.v. ipilimumab (4 cycles) combined with i.v. nivolumab (continuous). | Drug | Group 2 - Conventional treatment |
Primary outcome
Immunological effects
Time frame: 13 weeks
To determine the systemic immunological effects of standard i.v nivolumab combined with a single dose of 20 mg ipilimumab locally administered i.d. or systemic i.v. administration of standard of care dose ipilimumab as determined with the frequency and functionality of CD4+ and CD8+ T cells in peripheral blood cells.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 May 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
The record lists no contact. Use the official record to reach the sponsor.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Group 1 - Intradermal ipilimumab and Group 2 - Conventional treatment in people with Melanoma (Skin Cancer), run by Amsterdam UMC, location VUmc.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 29 May 2026. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Immunological effects (time frame: 13 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 May 2026.