Evaluation of EIK1001 and Pembrolizumab Versus Placebo and Pembrolizumab in Advanced Melanoma: A Randomized, Double-Blind, Phase 2/3 Study

The primary objective of this study is to evaluate the **efficacy** and **safety** of various doses of EIK1001 in combination with **pembrolizumab** for the treatment of advanced melanoma. This includes dose optimization to determine the most effective and safe dosage. Additionally, the study aims to compare the **progression-free survival (PFS)** and **overall survival (OS)** of patients receiving EIK1001 plus pembrolizumab versus those receiving a placebo plus pembrolizumab, as assessed by blinded independent central review (BICR). The clinical relevance of these objectives lies in potentially improving survival outcomes and establishing a new first-line therapy for advanced melanoma.

Secondary objectives include:

• Evaluating the safety and tolerability of the selected dose of EIK1001 plus pembrolizumab compared to placebo plus pembrolizumab.
• Assessing the objective response rate (ORR) and duration of response (DOR) according to RECIST 1.1 by BICR.
• Evaluating PFS, ORR, and DOR according to RECIST 1.1 as assessed by the investigator.
• Assessing DOR according to RECIST 1.1 as evaluated by the investigator for dose optimization.
• Evaluating PFS according to RECIST 1.1 as assessed by the investigator and overall survival (OS) for dose optimization, noting that this is not part of the dose selection interim analysis.

The clinical trial involves a total of **469 participants** diagnosed with **Advanced Melanoma**. The study population includes both male and female subjects, aged 18 years and older, who are eligible for standard therapy with pembrolizumab. Participants were selected based on their ability to provide informed consent and their willingness to adhere to contraceptive guidelines throughout the study. The trial includes individuals with a life expectancy of at least three months and those with histologically or cytologically confirmed Stage 3 (unresectable) or Stage 4 metastatic melanoma. Participants must have completed prior radiotherapy at least two weeks before the study treatment and have an **ECOG Performance Status** of 0 to 1. Adequate organ and marrow function is required, as defined by normal laboratory tests. The trial population also includes individuals with known BRAF V600 mutation status or those consenting to mutation testing. The study does not exclude vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed as a **randomized**, **double-blind**, active comparator-controlled, adaptive Phase 2/3 study. It aims to evaluate the safety and efficacy of EIK1001 in combination with **pembrolizumab** versus placebo and pembrolizumab as first-line therapy in participants with advanced melanoma. The trial is expected to commence recruitment on January 1, 2025, and conclude by May 30, 2030. Participants will be involved in the study for a maximum treatment period of 24 months, with the primary endpoints focusing on objective response, progression-free survival (PFS), and overall survival (OS).

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, life expectancy, and disease stage. Participants must have histologically or cytologically confirmed Stage 3 (unresectable) or Stage 4 metastatic melanoma and meet other inclusion criteria, including adequate organ function and a negative pregnancy test for women of childbearing potential. Following the screening, participants will be randomized to receive either EIK1001 with pembrolizumab or a matching placebo with pembrolizumab, administered intravenously.

Subsequent follow-up visits will be scheduled to monitor the participants' response to treatment, assess adverse events, and ensure compliance with the study protocol. These visits will include clinical evaluations, imaging studies, and laboratory tests to measure disease progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The end-of-study visit will occur after the completion of the treatment period or upon early termination due to disease progression, unacceptable toxicity, or withdrawal of consent.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in their best interest. The trial's adaptive design allows for modifications based on interim analyses, ensuring the study's objectives are met efficiently while maintaining participant safety. The trial's primary objective is to optimize the dose of EIK1001 and assess its impact on PFS and OS compared to the control group, with secondary endpoints evaluating additional safety and efficacy measures.

The clinical trial involves the administration of **Pembrolizumab**, a monoclonal antibody used as an immunotherapy agent. Pembrolizumab is provided in a pharmaceutical form identified as PHF00230MIG and is administered intravenously. The dosage for Pembrolizumab is set at a maximum of 200 mg per administration, with a total maximum dose of 7000 mg over the treatment period. The treatment is scheduled to be administered every three weeks for a maximum treatment period of 24 months. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to Pembrolizumab, the trial includes the investigational drug **EIK1001**, which is a solution for injection with a concentration of 1.0 mg/mL free base equivalent. The active substance in EIK1001 is **Resiquimod Sulfate**, a chemical compound. EIK1001 is also administered intravenously, and the dosing regimen will be optimized during the trial to evaluate its efficacy and safety in combination with Pembrolizumab. The maximum treatment period for EIK1001 is 24 months, and participant compliance will be closely monitored.

The study also utilizes a **matching placebo** to serve as a comparator in the trial. The placebo is designed to match the appearance and administration route of the active treatments but contains no active pharmaceutical ingredients. The placebo is administered intravenously in a manner consistent with the active treatments to maintain the double-blind nature of the study. The use of a placebo allows for a controlled comparison to assess the efficacy and safety of the investigational treatments.

The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include **Objective Response (OR)**, defined as participants who demonstrate confirmed complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by the Investigator. Additionally, progression-free survival (PFS) will be measured, defined as the time from randomization to documented progressive disease per RECIST 1.1 by blinded independent central review (BICR) or death due to any cause, whichever occurs first. Overall survival (OS) is also a primary endpoint, defined as the time from randomization to death due to any cause.

Secondary endpoints include adverse events (AEs) and discontinuation of study treatment due to any AE. The duration of response (DOR) will be evaluated, defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause, according to RECIST 1.1 by BICR. PFS, OR, and DOR will also be assessed according to RECIST 1.1 by the Investigator. The trial will utilize these endpoints to compare the efficacy of EIK1001 in combination with pembrolizumab versus placebo and pembrolizumab in participants with advanced melanoma.