Evaluation of Intravenous Fosnetupitant/Palonosetron for Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients Undergoing Highly Emetogenic Chemotherapy

The primary objective of this study is to confirm the pharmacokinetic (**PK**) profile of a single dose of intravenous (**IV**) fosnetupitant in pediatric cancer patients undergoing chemotherapy. This is crucial to ensure that the expected netupitant exposure aligns with previous oral NEPA studies, thereby validating the dosing regimen for effective prevention of **chemotherapy-induced nausea and vomiting** (**CINV**). Additionally, the study aims to assess the safety and tolerability of repeated IV NEPA administration in pediatric patients, which is essential for ensuring patient safety during treatment.

Secondary objectives include:

• Assessing the safety and tolerability of a single IV NEPA infusion compared to IV fosaprepitant/ondansetron in patients aged ≥6 months.
• Evaluating the PK profile of fosnetupitant, netupitant, and palonosetron in the pediatric population following single and repeated dosing of IV NEPA.
• Investigating the PK/pharmacodynamic (PD) correlation between netupitant exposure and antiemetic efficacy in pediatric cancer patients.
• Assessing the efficacy of IV NEPA in preventing acute, delayed, and overall CINV compared to IV fosaprepitant + IV ondansetron in patients aged ≥6 months to <18 years.
• Evaluating the efficacy of repeated IV NEPA dosing in preventing CINV in patients aged 0 months to <18 years following multi-day highly emetogenic chemotherapy (HEC).
• Characterizing the PK profile of fosnetupitant, netupitant, and palonosetron by a population PK approach and evaluating their accumulation following multiple IV NEPA administrations.
• Assessing the safety and tolerability of repeated IV NEPA administration in preventing emesis in pediatric cancer patients receiving multi-day HEC.

The clinical trial involves a total of **40 participants** who are pediatric patients experiencing **chemotherapy-induced nausea and vomiting**. The study population includes both male and female subjects, ranging in age from **3 months to less than 18 years**. Participants were selected based on specific criteria, including weight and health status, ensuring that those with non-clinically significant abnormal laboratory values or clinically relevant values that do not jeopardize safety could be included. The trial also considers patients with known hepatic or renal impairments, provided certain laboratory thresholds are met, and those with a history or predisposition to cardiac abnormalities, as long as safety is not compromised. The study population is characterized by a predicted life expectancy of at least 3 months and, for those aged 10 years and older, an Eastern Cooperative Oncology Group Performance Status of 2 or less. The trial does not specify particular lifestyle considerations such as diet or physical activity. Participants are required to be eligible for receiving high-emetic chemotherapy (HEC), either single-day or multi-day, depending on the cohort. The trial includes a vulnerable population, reflecting the pediatric nature of the study group.

The clinical trial is designed to evaluate the pharmacokinetics, safety, and efficacy of **IV NEPA** (fosnetupitant/palonosetron) in preventing **chemotherapy-induced nausea and vomiting** (CINV) in pediatric cancer patients undergoing highly emetogenic chemotherapy (HEC). This study is structured in two parts: Part I is an open-label, randomized, single-dose study, while Part II is a double-blind, randomized, repeated-dose study. The trial is expected to conclude by December 31, 2027, with recruitment starting on May 5, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, weight, and medical history. The trial includes multiple follow-up visits to monitor safety and efficacy, with specific attention to pharmacokinetic parameters and adverse events. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the treatment. The expected duration of participant involvement varies, with Part I involving a single cycle and Part II involving repeated cycles of treatment.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial aims to demonstrate the non-inferiority of IV NEPA compared to other antiemetic regimens, with primary endpoints focusing on netupitant exposure and safety parameters. Secondary endpoints include additional pharmacokinetic analyses and efficacy measures such as the proportion of patients with complete response (CR) during the delayed phase of emesis.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Sodium Chloride Injection BP 0.9% w/v** is utilized as a solvent and diluting agent. It is provided in an **injection** form and administered via **intravenous infusion**. The product is manufactured by Hameln Pharma Ltd and is of chemical origin. The maximum treatment period for this solution is five days, although it does not have a specified maximum daily or total dose amount.

**IVEMEND 150 mg powder for solution for infusion** contains the active substance **fosaprepitant**. This medication is provided as a **powder for solution for infusion** and is administered through **intravenous use**. Manufactured by Merck Sharp & Dohme B.V., it is of chemical origin. The maximum daily dose is 150 mg, with a total maximum dose of 275 mg over a treatment period of three days.

The experimental treatment **fosnetupitant chloride 260 mg/palonosetron 1.5 mg** is a **concentrate for solution for infusion**. It contains the active substances **palonosetron hydrochloride** and **204-NETU**. This formulation is administered via **intravenous use** and is designed for pediatric use. The maximum daily dose is 20 ml, with a total maximum dose of 240 ml over a five-day treatment period. It is produced by Helsinn Healthcare SA and is of chemical origin.

Another experimental treatment, **fosnetupitant chloride 260 mg/palonosetron 2.5 mg**, is also a **concentrate for solution for infusion**. It contains the same active substances as the previous formulation and is administered through **intravenous use**. This pediatric formulation has a maximum daily dose of 3.2 ml and a total maximum dose of 9.6 ml over five days. It is also manufactured by Helsinn Healthcare SA and is of chemical origin.

**Ondansetrone Hikma 8 mg/4 ml Soluzione iniettabile** is a **solution for injection** containing the active substance **ondansetron**. This medication is administered via **intravenous use** and is produced by Hikma Farmacêutica (Portugal), S.A. The maximum daily dose is 24 mg, with a total maximum dose of 56 mg over a five-day treatment period. It is of chemical origin and serves as a comparator in the study.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint for Part I, Cohort 1, involves evaluating the **netupitant** exposure parameters, specifically the maximum concentration (Cmax) and the area under the plasma concentration-time curve from time zero to the last measurable timepoint (AUClast) and to infinity (AUCinf). For Part II, the primary endpoint is the proportion of patients achieving complete response (CR), defined as no emetic episodes and no rescue medication, during the delayed phase of emesis (24-120 hours post-chemotherapy) in Cycle 1.

Secondary efficacy endpoints include various pharmacokinetic (PK) parameters for netupitant and its metabolites, as well as for fosnetupitant and palonosetron. These parameters include Cmax, tmax, AUClast, AUC0-48, AUCinf, and others. Additionally, the trial will assess the proportion of patients with CR, no emetic episodes, no rescue medication, and time to treatment failure across both Part I and Part II. Population PK analysis will be conducted using samples from both cohorts and all age groups to characterize PK values for the involved substances. PK/PD correlations between netupitant and palonosetron exposure parameters and antiemetic efficacy parameters will also be evaluated.

Measurements will be collected at specified timepoints, including during the acute, delayed, and overall phases of emesis in Cycle 1 and repeated cycles. The trial will utilize pooled plasma concentration-time data from both Part I and Part II to evaluate population PK for the involved substances. The efficacy assessments will be conducted using validated scales and laboratory tests, ensuring a comprehensive evaluation of the trial's objectives.