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

22 maggio 2026 aggiornato da: C. Menke- van der Houven van Oordt, Amsterdam UMC, location VUmc

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.

Panoramica dello studio

Stato

Non ancora reclutamento

Condizioni

Intervento / Trattamento

Descrizione dettagliata

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

1. 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.

4. 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.

Tipo di studio

Interventistico

Iscrizione (Stimato)

18

Fase

  • Fase 2
  • Fase 1

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

  • Adulto
  • Adulto più anziano

Accetta volontari sani

No

Descrizione

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 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.

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 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.
  • 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.

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Trattamento
  • Assegnazione: Non randomizzato
  • Modello interventistico: Assegnazione parallela
  • Mascheramento: Nessuno (etichetta aperta)

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Sperimentale: Group 1 - Intradermal ipilimumab
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.
Droga: Group 1 - Intradermal ipilimumab
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).
Comparatore attivo: Group 2 - Conventional treatment
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.
Droga: Group 2 - Conventional treatment
Patients will be treated according to standard of care with i.v. ipilimumab (4 cycles) combined with i.v. nivolumab (continuous).

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Immunological effects
Lasso di tempo: 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.
13 weeks

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

Amsterdam UMC, location VUmc

Collaboratori

GE Healthcare

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio (Stimato)

1 luglio 2026

Completamento primario (Stimato)

1 luglio 2028

Completamento dello studio (Stimato)

1 luglio 2029

Date di iscrizione allo studio

Primo inviato

22 maggio 2026

Primo inviato che soddisfa i criteri di controllo qualità

22 maggio 2026

Primo Inserito (Effettivo)

29 maggio 2026

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Effettivo)

29 maggio 2026

Ultimo aggiornamento inviato che soddisfa i criteri QC

22 maggio 2026

Ultimo verificato

1 maggio 2026

Maggiori informazioni

Termini relativi a questo studio

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • 2026.0392
  • 2024-516545-39-00 (Ctis)

Informazioni su farmaci e dispositivi, documenti di studio

Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti

No

Studia un dispositivo regolamentato dalla FDA degli Stati Uniti

No

prodotto fabbricato ed esportato dagli Stati Uniti

No

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

Prove cliniche su Melanoma (cancro della pelle)

Prove cliniche su Group 1 - Intradermal ipilimumab

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Sedi

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