A Phase I/II Study of Pembrolizumab (MK-3475) in children with advanced melanoma or a PD-L1 positive advanced, relapsed or refractory solid tumor or lymphoma (KEYNOTE-051)

The primary objective of this study is to define the rate of **Dose-Limiting Toxicities (DLTs)** at the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of pembrolizumab when administered as monotherapy. This is clinically relevant as it helps establish the safety profile and optimal dosing regimen for pembrolizumab in pediatric patients with advanced melanoma or PD-L1 positive advanced, relapsed, or refractory solid tumors or lymphoma. Additionally, the study aims to determine the safety and tolerability of pembrolizumab based on adverse events (AEs) and clinical and laboratory measures, and to evaluate its antitumor activity based on response evaluation criteria in solid tumors (RECIST) 1.1 and Objective Response Rate (ORR) per site assessment.

Secondary objectives include:

• Characterizing the pharmacokinetics and pharmacodynamics of pembrolizumab.
• Evaluating clinical activity as measured by Duration of Response (DOR), Disease Control Rate (DCR), and Progression-Free Survival (PFS) by RECIST 1.1, and overall survival.
• Assessing antitumor activity by IWG 2007 response criteria, including ORR, DOR, and PFS per site and Blinded Independent Central Review (BICR) assessment, and overall survival.
• Assessing at least five biomarkers such as NRAS, BRAF, MEK, KIT, PDGF, TP53, RB1, BRCA1, Akt phosphorylation, IL-17, and PD-L1 at the time of progression.
• Evaluating changes in vaccinated antibody concentrations and memory B- and T-cell counts.
• Evaluating the relationship between baseline tumor PD-L1 expression and clinical efficacy outcomes.
• Assessing PD-L1 and PD-L2 expression and other biomarkers to compare pre-pembrolizumab PD-L1 expression in tissue biopsies for pembrolizumab responders versus nonresponders.

The clinical trial involves a total of **79 participants** who are children aged between **6 months and less than 18 years**. The study population includes both **male and female** subjects, with no specific vulnerable populations selected. Participants were chosen based on their diagnosis of advanced melanoma, or advanced, relapsed, or refractory PD-L1 positive malignant solid tumors, or other lymphomas, including relapsed or refractory classical Hodgkin lymphoma (rrcHL), and advanced, relapsed, or refractory microsatellite-instability-high (MSI-H) solid tumors. The trial also includes any advanced relapsed or refractory solid tumor with a tumor mutational burden of ≥10 mutations per megabase (TMB-H), excluding MSI-H/deficient mismatch repair (dMMR) tumors. The selection criteria required participants to have histologically or cytologically documented, locally advanced, or metastatic solid malignancy or lymphoma that is incurable and has failed prior standard therapy, or for which no standard therapy exists or is considered appropriate. Participants were required to demonstrate adequate organ function and have measurable disease based on RECIST 1.1 criteria. Lifestyle considerations such as diet, physical activity, or habits were not specified in the trial data provided.

The clinical trial is designed to evaluate the safety, tolerability, and antitumor activity of **pembrolizumab** in pediatric patients with advanced melanoma or PD-L1 positive advanced, relapsed, or refractory solid tumors or lymphoma. This is a Phase I/II, randomized, double-blind, controlled trial. The trial aims to define the rate of dose-limiting toxicities at the maximum tolerated dose or maximum administered dose of pembrolizumab when administered as monotherapy. The study will also assess the objective response rate based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the International Working Group (IWG) response criteria for relapsed or refractory classical Hodgkin lymphoma (rrcHL).

The trial is expected to run from January 16, 2023, to May 6, 2025. Participants will be involved in the study for the duration of the trial, with the possibility of early termination if they experience adverse events or if the study drug is discontinued due to safety concerns. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits every 12 weeks to monitor safety and efficacy, and an end-of-study visit to assess the overall outcomes and any long-term effects of the treatment.

Inclusion criteria require participants to be between 6 months and less than 18 years of age, with histologically or cytologically documented, locally advanced, or metastatic solid malignancy or lymphoma that is incurable and has failed prior standard therapy. Adequate organ function and measurable disease based on RECIST 1.1 are also required. Exclusion criteria are not specified in the provided data. The trial will monitor primary endpoints such as the objective response rate and the number of participants experiencing adverse events, while secondary endpoints include progression-free survival and overall survival.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name **KEYTRUDA**. This experimental medication is provided as a **25 mg/mL concentrate for solution for infusion**. The pharmaceutical form is a **solution for infusion**, and it is administered via the **intravenous** route. The frequency of administration is determined by the study protocol, which aims to evaluate the safety, tolerability, and antitumor activity of pembrolizumab in pediatric patients with advanced melanoma or PD-L1 positive advanced, relapsed, or refractory solid tumors or lymphoma. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code **L01FF02**. The medication is produced by **Merck Sharp & Dohme BV** and is identified by several synonyms, including Lambrolizumab, MK-3475, SCH-900475, and ABP 234.

In this study, pembrolizumab is administered as monotherapy, with no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments being utilized. The trial's primary objectives include defining the rate of dose-limiting toxicities at the maximum tolerated dose or maximum administered dose, determining the safety and tolerability based on adverse events, and evaluating the antitumor activity based on response evaluation criteria in solid tumors (RECIST) 1.1. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol and to accurately assess the therapeutic outcomes of pembrolizumab.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)** by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 per site assessment, ORR by RECIST 1.1 per site or BIRC assessment for MSI-H or TMBH solid tumors, and ORR by International Working Group (IWG) Response Criteria (Cheson, 2007) per BICR assessment for the relapsed refractory classical Hodgkin lymphoma (rrcHL) cohort. Additionally, the number of participants with Dose-Limiting Toxicities (DLTs), the number of participants experiencing adverse events (AEs), and the number of participants discontinuing the study drug due to AEs will be evaluated.

Secondary endpoints include the Duration of Response (DOR) per RECIST 1.1 by site assessment for advanced melanoma, solid tumors, and other lymphomas, as well as DOR per IWG 2007 (Cheson, 2007) response by BICR assessment for the rrcHL cohort. Progression-free survival (PFS) using RECIST 1.1 criteria by site assessment and PFS using IWG 2007 criteria by BICR assessment for the rrcHL cohort will also be measured. Additional secondary endpoints include Disease Control Rate by RECIST 1.1 using site assessment, Overall Survival, and the Area Under the Concentration Curve (AUC) for pembrolizumab.

The antitumor activity of pembrolizumab will be evaluated based on these criteria, with assessments conducted every 12 weeks. The trial will utilize site assessments and BICR assessments to ensure accurate and consistent evaluation of the efficacy parameters. The study aims to provide comprehensive data on the efficacy of pembrolizumab in treating advanced melanoma, PD-L1-positive advanced, relapsed, or refractory solid tumors, and lymphoma in pediatric patients.