Evaluation of Palonosetron and Netupitant as Antiemetic Therapy in Chemotherapy-Naïve Endometrial Cancer Patients Receiving Paclitaxel-Carboplatin Regimen.

The primary objective of this study is to evaluate the **effectiveness** of a single oral dose of NEPA in achieving a complete response (CR), defined as no emesis and no rescue medication, during the overall phase (0-120 hours) of cycle 1 in chemotherapy-naïve patients with endometrial cancer receiving a regimen of paclitaxel and carboplatin, with or without immunotherapy. This is clinically relevant as it aims to improve the management of chemotherapy-induced nausea and vomiting (CINV), which can significantly impact patient quality of life and treatment adherence.

Secondary objectives include:

• Assessing the effectiveness of NEPA in terms of CR and complete control (CC: no rescue medication, no emesis, and no nausea with a VAS score of <25 mm) during the acute (0-24 hours), delayed (>24 to 120 hours), and overall (0-120 hours) phases after the start of chemotherapy in each cycle.
• Evaluating the effectiveness of NEPA in terms of no rescue medication, no emesis, and no significant nausea (VAS score of <25 mm) during the acute, delayed, and overall phases after the start of chemotherapy in each cycle.
• Determining the effectiveness of NEPA in terms of CR and complete control during the acute, delayed, and overall phases according to the Patient Emetogenicity Risk Profile assessed with the CINV Risk Assessment tool in patients with endometrial cancer receiving paclitaxel and carboplatin with or without immunotherapy.
• Evaluating the safety of NEPA when administered in multiple treatment cycles in patients with endometrial cancer receiving paclitaxel and carboplatin with or without immunotherapy.
• Assessing the quality of life (QoL) of patients with endometrial cancer treated with paclitaxel and carboplatin regimen receiving NEPA as antiemetic treatment, in terms of FLIE scores during each cycle.

The clinical trial focuses on evaluating the effectiveness of a single oral dose of NEPA in chemotherapy-naïve patients with **endometrial cancer**. The study population consists exclusively of female participants, as male subjects are not included. Participants are adults, with an age range corresponding to categories 3 and 4, which typically includes individuals aged 18 years and older. All participants have histologically or cytologically confirmed endometrial cancer and are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, indicating they are ambulatory and capable of self-care. The trial does not include vulnerable populations. Participants must have adequate organ function to receive taxane-platinum combination therapy, with or without immunotherapy, as per clinical practice and the treating physician's opinion. The sponsor has not provided the total number of participants involved in the trial. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the effectiveness of a single oral dose of **NEPA** in achieving a complete response in chemotherapy-naïve patients with **endometrial cancer** receiving a combination of **paclitaxel** and **carboplatin**, with or without immunotherapy. This trial is a randomized, double-blind, controlled study, categorized as a Phase IV clinical trial. The estimated duration of the trial is from December 2023 to June 2025, with participant involvement expected to last up to four weeks, depending on the treatment cycle.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, cancer diagnosis, and organ function. The primary endpoint is the proportion of patients achieving a complete response, defined as no emesis and no rescue medication, during the overall phase (0-120 hours) at cycle 1. Secondary endpoints include the assessment of complete response and control during acute, delayed, and overall phases of each cycle, as well as the safety and tolerability of the study drug based on adverse event reports and clinical evaluations.

Follow-up visits will occur throughout the treatment period to monitor the patient's response to the medication and any adverse effects. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or withdrawal of consent by the participant. The trial aims to provide valuable insights into the management of chemotherapy-induced nausea and vomiting in patients with endometrial cancer.

The clinical trial involves the administration of **Akynzeo 300 mg/0.5 mg hard capsules**, which contain the active substances **palonosetron** and **netupitant**. These capsules are formulated as hard capsules and are administered orally. The dosage is set at one unit per day, with a maximum treatment period of four days. Akynzeo is classified as an antiemetic and is used to prevent nausea and vomiting in patients undergoing chemotherapy. The product is manufactured by Helsinn Birex Pharmaceuticals Ltd. and is authorized for use in several European countries.

Another treatment used in the trial is **Tecentriq 1,200 mg concentrate for solution for infusion**, containing the active substance **atezolizumab**. This medication is administered intravenously as a solution for infusion. The maximum daily and total dose is 1,200 mg, with a treatment period of one day. Tecentriq is a monoclonal antibody produced by Roche Registration GmbH and is used as an auxiliary treatment in the trial.

**KEYTRUDA 25 mg/mL concentrate for solution for infusion** is also included in the trial, with the active substance **pembrolizumab**. This solution is administered intravenously, with a maximum daily and total dose of 200 mg over a one-day treatment period. KEYTRUDA, a monoclonal antibody, is manufactured by Merck Sharp & Dohme B.V. and serves as an auxiliary treatment in the study.

The trial incorporates **Decadron "4 mg/1 ml Soluzione iniettabile"**, which contains **dexamethasone phosphate**. This solution for injection is administered as an injectable solution, with a maximum daily and total dose of 12 mg over a four-day treatment period. Decadron is an anti-inflammatory medication produced by I.B.N. Savio S.R.L. and is used as an auxiliary treatment in the trial.

**Paclitaxel Kabi 6 mg/ml concentrato per soluzione per infusione** is another treatment used, containing the active substance **paclitaxel**. This chemotherapy drug is administered via infusion, with a maximum daily and total dose of 175 mg/m² over a four-day treatment period. Manufactured by Fresenius Kabi Italia S.R.L., it is used as an auxiliary treatment in the study.

**CARBOPLATINO Pfizer 10 mg/ml soluzione per infusione** is included in the trial, with the active substance **carboplatin**. This chemotherapy drug is administered via infusion, with a maximum daily and total dose of 400 mg/m² over a four-day treatment period. Produced by Pfizer Italia S.R.L., it serves as an auxiliary treatment in the study.

Lastly, **JEMPERLI 500 mg concentrate for solution for infusion** is used, containing the active substance **dostarlimab**. This monoclonal antibody is administered intravenously, with a maximum daily and total dose of 500 mg over a one-day treatment period. JEMPERLI is manufactured by GlaxoSmithKline (Ireland) Limited and is used as an auxiliary treatment in the trial.

Efficacy in this clinical trial will be assessed primarily by evaluating the proportion of patients achieving a **complete response (CR)**, defined as no emesis and no rescue medication, during the overall phase (0-120 hours) at cycle 1. This primary endpoint will be measured in chemotherapy-naïve patients with endometrial cancer receiving a combination of paclitaxel and carboplatin, with or without immunotherapy. Secondary endpoints include the proportion of patients achieving complete response and complete control during the acute (0-24 hours), delayed (>24 to 120 hours), and overall (0-120 hours) phases of each chemotherapy cycle. Additionally, the trial will assess the proportion of patients achieving no rescue medication, no emesis, and no significant nausea, defined as a Visual Analog Scale (VAS) score of less than 25 mm, during these phases.

The efficacy parameters will be collected and analyzed using patient-reported outcomes and clinical assessments. The Patient Emetogenicity Risk Profile will be evaluated with a 10-item Chemotherapy-Induced Nausea and Vomiting (CINV) Risk Assessment tool. The safety and tolerability of the study drug, NEPA, will also be evaluated based on adverse event reports, physical examination results, including vital signs, and clinical laboratory results. The occurrence, nature, and severity of adverse events will be documented to ensure comprehensive safety monitoring throughout the trial.