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

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

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