A clinical trial to investigate immunotherapy (IMO-2125) in the skin of patients with a melanoma which is at least 2 millimeters thick

Rationale: Currently, there is no widely used adjuvant treatment available to improve survival after surgical excision of a primary melanoma. We previously described loco-regional and systemic immune stimulation as well as favourable clinical outcomes in terms of sentinel lymph node (SLN) tumor status and recurrence-free survival (RFS) in patients with clinical stage I-II melanoma who received a low dose of the TLR-9 agonist CPG7909 (CpG-B ODN) intradermally at the excision site of the primary tumor prior to the SLN biopsy (SNB). We now investigate the clinical activity of a next-generation CpG ODN, IMO-2125, and its ability to induce loco-regional and systemic immune stimulation in clinical T3-4N0M0 (cT3-4N0M0) melanoma patients.

Objective: The primary objective is to investigate whether local administration of a single dose of IMO-2125 at the primary melanoma excision site results in decreased tumor positive SLN rates. The secondary objectives are to investigate 1) whether a single dose of IMO-2125 induces a loco-regional and systemic immune response and 2) RFS and overall survival (OS) at 5 and 10 years after SNB.
Study design: A randomized single-center double-blind and placebo-controlled Phase II clinical trial.

Study population: Adult patients with cT3-4N0M0 melanoma who are scheduled to undergo a combined re-excision and sentinel node biopsy (SNB) procedure.

Intervention: Seven days before SNB, patients will receive an intradermal injection, directly adjacent to the excision site of the primary tumor, of 8mg IMO-2125 dissolved in 1 mL saline (0.9% sodium chloride) (n=107) or 1mL plain saline alone (placebo control n=107). 10 patients from each treatment arm will be enrolled in an immune monitoring sub-study.

Main study parameters/endpoints: SLN tumor status (positive or negative) 7 days after injection; SLN and systemic immune profile with emphasis on recruitment and/or activation in the SLN of dendritic cell (DC), effector-T cell and Treg subsets, and melanoma antigen-specific T cell responses in peripheral blood; RFS and OS at 5 and 10 years after treatment

Nature and extent of the burden and risks associated with participation and benefit: The burden associated with participation comprises one intradermal injection at the VU University medical center; and a follow-up contact at 5 and 10 years after SNB. For the 20 patients in the immune monitoring sub-study, 50 ml heparinized blood will be drawn at 4 time-points that will be planned together with standard treatment visits if possible but can result in 2 additional visits. The most common adverse events (AEs) seen with IMO-2125 are injection site reactions (ISR) and flu-like symptoms. In general, these reactions occur early and resolve within 48 hrs with non-specific measures. We do not expect to see any serious adverse events with IMO-2125 at this dose level. Potential benefits of IMO-2125 treatment in this trial may include SLN tumor clearance and a longer recurrence-free and overall survival.

Intradermal IMO-2125 treatment can result in a loco-regional anti-tumor immune response and SLN tumor clearance and a longer recurrence-free and overall survival in patients with cT3-4N0M0 melanoma.

The rate of tumor positive SLN seven days after the experimental treatment.



Frequency and activation state of lymph node resident (LNR) conventional dendritic cells (DC) and melanoma antigen-specific T cell responses in the SLN at 7 days after the experimental treatment and peripheral blood before and 7, 21 and 13 weeks after the experimental treatment.



RFS at 5 and 10 years after SNB.



OS at 5 and 10 years after SNB.

In the treatment arm, patients will be intradermally injected with 8 mg IMO-2125, in 1 mL saline (0.9% sodium chloride) one week prior to sentinel node biopsy (SNB). In the placebo control arm, patients will be intradermally injected with 1 mL plain saline (0.9% sodium chloride) only one week prior to SNB.