Phase 1/2 Study on Safety and Efficacy of Zilovertamab Vedotin in Pediatric and Young Adult Patients with Hematologic Malignancies or Solid Tumors

The primary objective of this study is to evaluate the **safety** and **tolerability** of zilovertamab vedotin monotherapy in pediatric participants aged 1 to less than 18 years. Additionally, the study aims to assess the preliminary antitumor activity of zilovertamab vedotin monotherapy, as evaluated by investigators, in participants from birth to less than 18 years for B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL)/Burkitt lymphoma, and neuroblastoma, and from birth to 25 years for Ewing sarcoma. These objectives are clinically relevant as they address the potential of zilovertamab vedotin to provide a new therapeutic option for young patients with these hematologic malignancies or solid tumors, focusing on both safety and initial efficacy.

Secondary objectives include:

• Determining the pharmacokinetic (PK) profile of zilovertamab vedotin in both Part 1 and Part 2 of the study.
• Evaluating the safety and tolerability of zilovertamab vedotin monotherapy in participants from birth to less than 18 years for B-ALL, DLBCL/Burkitt lymphoma, and neuroblastoma, and from birth to 25 years for Ewing sarcoma.
• Assessing the immunogenicity potential of zilovertamab vedotin in both Part 1 and Part 2.
• Evaluating the duration of response (DOR) per investigator assessment by tumor type in both Part 1 and Part 2.
• Evaluating the proportion of participants by tumor type who become eligible for transplant/CAR-T therapy while on treatment with zilovertamab vedotin in both Part 1 and Part 2.

The clinical trial involves a total of **63 participants** diagnosed with **hematologic malignancies** or **solid tumors** in pediatric and young adults. The study population includes both male and female subjects, ranging from birth to under 18 years of age for conditions such as B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL)/Burkitt lymphoma, and neuroblastoma, and extends up to 25 years for Ewing sarcoma. Participants were selected based on the presence of advanced, relapsed, or refractory disease that is incurable, with prior therapies being unsuccessful or standard therapies deemed unavailable or inappropriate. The trial includes individuals with confirmed diagnoses of B-ALL, DLBCL/Burkitt lymphoma, neuroblastoma, or Ewing sarcoma, who have exhausted all therapies of known clinical benefit. The study population is considered vulnerable, and the trial aims to evaluate the safety and tolerability of zilovertamab vedotin monotherapy, as well as its preliminary antitumor activity. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **safety** and efficacy of **zilovertamab vedotin** in pediatric and young adult participants with hematologic malignancies or solid tumors. This study is structured as a Phase 1/2 trial, employing a randomized, double-blind, and controlled methodology to ensure robust and unbiased results. The trial is expected to commence on March 6, 2024, and conclude by March 31, 2029, encompassing a comprehensive duration to assess both short-term and long-term outcomes.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as advanced, relapsed, or refractory disease that is incurable and for which prior therapy was unsuccessful. The trial will include multiple follow-up visits to monitor the participants' response to the treatment and any adverse events. The end-of-study visit will be conducted to gather final data and ensure participant safety post-treatment.

The expected length of participant involvement will vary depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities, adverse events necessitating discontinuation, or if the participant chooses to withdraw consent. The primary endpoints focus on the number of participants experiencing dose-limiting toxicities, adverse events, and objective response rates for specific conditions such as B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Secondary endpoints include pharmacokinetic parameters and the incidence of antidrug antibodies.

The clinical trial involves the administration of **Zilovertamab vedotin**, an experimental medication developed by Merck & Co. Inc. This investigational product is classified as a **biological** agent and is presented in the pharmaceutical form of a **solution for infusion**. The active substance, **zilovertamab vedotin**, is a protein-based compound. The medication is administered via **intravenous infusion**. The trial aims to evaluate the safety, tolerability, and preliminary antitumor activity of zilovertamab vedotin monotherapy in pediatric and young adult participants with hematologic malignancies or solid tumors. The dosing schedule and frequency of administration are determined by the study protocol, and participant compliance is monitored throughout the trial.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus remains solely on the investigational product, zilovertamab vedotin, to assess its effects in the specified patient population. The trial does not include a pediatric formulation of the drug, and it is not designated as an orphan drug. The study protocol ensures rigorous monitoring of drug administration and participant adherence to the treatment regimen to maintain the integrity of the trial data.

The clinical trial aims to assess the efficacy of **Zilovertamab Vedotin** in pediatric and young adult participants with hematologic malignancies or solid tumors. Efficacy will be evaluated through several primary and secondary endpoints. The primary endpoints include the objective response (OR) for participants with B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL)/Burkitt lymphoma, neuroblastoma, and Ewing sarcoma. These endpoints will be assessed in both Part 1 and Part 2 of the study.

Secondary endpoints focus on pharmacokinetic parameters such as the area under the curve (AUC), maximum plasma concentration (Cmax), plasma trough concentration (Ctrough), and apparent terminal half-life (t1/2) of the total antibody, antibody-drug conjugate (ADC), and monomethyl auristatin E (MMAE). Additionally, the incidence of antidrug antibodies (ADAs) to Zilovertamab Vedotin, duration of response (DOR), and the percentage of participants receiving stem cell transplant (SCT) or chimeric antigen receptor T (CAR-T) therapy are also evaluated.

The trial will collect data on these endpoints at specified intervals throughout the study duration, with the estimated end date set for March 31, 2029. The study will utilize validated scales and laboratory tests to ensure accurate and reliable measurement of these parameters. The analysis will be conducted in accordance with the trial protocol to determine the efficacy of the investigational product in the target population.