Phase II Randomized Controlled Trial of Intradermal Tilsotolimod Sodium in Patients with pT3-4 cN0M0 Melanoma

The primary objective of this randomized controlled Phase II clinical trial is to evaluate whether the **local administration** of IMO-2125 (tilsotolimod sodium) results in lower rates of tumor-positive sentinel lymph nodes (SLN) in patients with pT3-4 cN0M0 melanoma. This is clinically relevant as a reduction in tumor-positive SLN could indicate a decrease in metastatic spread, potentially improving patient outcomes and guiding treatment strategies.

Secondary objectives include:

• Investigating if locally administered IMO-2125 can increase the frequency and activation state of lymph node-resident conventional dendritic cell subsets and melanoma antigen-specific T cells in the SLN and peripheral blood of patients with pT3-4 cN0M0 melanoma.
• Comparing recurrence-free survival (RFS) and overall survival (OS) at 18 months, 24 months, 36 months, 5 years, and 10 years after the sentinel node biopsy (SNB) in patients with pT3-4 cN0M0 melanoma who received either 8 mg IMO-2125 or placebo.

The clinical trial involves participants diagnosed with **pT3-4 cN0M0 melanoma**, focusing on individuals aged 18 years and older. Both male and female subjects are included, with no vulnerable populations selected for this study. Participants are required to have a WHO Performance Status of 0 or 1, indicating they are in relatively good health despite their condition. The study population was selected based on specific inclusion criteria, such as having a histologically confirmed primary malignant melanoma cutis with a Breslow tumor depth greater than 2.0 mm. Additionally, women of childbearing potential and fertile men must agree to use effective contraceptive methods during the study period. The sponsor has not provided information regarding the total number of participants in this trial.

The clinical trial is a **randomized controlled Phase II** study designed to evaluate the efficacy of intradermal administration of **IMO-2125** (tilsotolimod sodium) in patients with **pT3-4 cN0M0 melanoma**. The primary objective is to determine if local administration of the investigational product results in lower rates of tumor-positive sentinel lymph nodes (SLN). The trial is expected to run from June 2019 to June 2032, with the primary endpoint being the rate of tumor-positive SLN seven days post-treatment. Secondary endpoints include the frequency and activation state of lymph node resident conventional dendritic cells and melanoma antigen-specific T cell responses, as well as recurrence-free survival (RFS) and overall survival (OS) at various time points up to 10 years post-sentinel node biopsy (SNB).

Participants will be involved in the study for a maximum treatment period of one day, with a follow-up period extending up to 10 years for long-term outcomes. The study includes an initial screening visit to confirm eligibility, which requires participants to be at least 18 years old, have a WHO Performance Status of ≤1, and a histologically confirmed primary malignant melanoma with a Breslow tumor depth greater than 2.0 mm. Women of childbearing potential and fertile men must agree to use effective contraceptive methods from screening until at least 90 days after administration of IMO-2125.

Following the screening visit, eligible participants will be randomized to receive the investigational product via **intradermal injection**. The study design is double-blind, ensuring that neither the participants nor the investigators know which treatment is being administered. Follow-up visits will be scheduled to assess the primary and secondary endpoints, with the end-of-study visit marking the conclusion of the participant's involvement. Conditions that may lead to early termination from the study include withdrawal of consent, non-compliance with the study protocol, or adverse events that necessitate discontinuation of treatment.

The clinical trial involves the administration of **IMO-2125**, also known as **tilsotolimod sodium**, which is an investigational medication formulated as a **solution for injection**. The active substance, **tilsotolimod sodium**, is derived from nucleic acid and is administered via **intradermal injection**. The dosing regimen for this trial specifies a maximum daily dose of 8 mg, with the total dose not exceeding 8 mg over the course of the treatment period, which is limited to one day. The trial aims to evaluate the effects of local administration of IMO-2125 in patients diagnosed with clinical cT3-4N0M0 melanoma.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of the investigational product, IMO-2125. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial is designed to assess the potential of IMO-2125 to reduce the rates of tumor-positive sentinel lymph nodes in the specified patient population.

Efficacy in this clinical trial will be assessed primarily by evaluating the rate of tumor-positive sentinel lymph nodes (SLN) seven days following the administration of the investigational treatment, **IMO-2125** (tilsotolimod sodium), in patients with clinical cT3-4N0M0 melanoma. This primary endpoint will provide insight into the effectiveness of the local administration of the drug in reducing tumor presence in SLNs.

Secondary endpoints will include the frequency and activation state of lymph node resident conventional dendritic cells and melanoma antigen-specific T cell responses in the SLN and peripheral blood. Additionally, recurrence-free survival (RFS) and overall survival (OS) will be measured at multiple timepoints: 18 months, 24 months, 36 months, 5 years, and 10 years post-sentinel node biopsy (SNB). These secondary endpoints will help to further elucidate the long-term efficacy and immunological impact of the treatment.