Study With IV NEPA (Fosnetupitant/Palonosetron) for the Prevention of Chemotherapy-induced Nausea and Vomiting in Paediatric Cancer Patients Undergoing Highly Emetogenic Chemotherapy (HEC)

Inclusion Criteria:

The following inclusion criteria must be checked prior to study inclusion:

1. Signed written Informed Consent Form (ICF) by parent(s)/legal guardian of thepaediatric patient in compliance with the local laws and regulations. In addition,the signed children's Assent Form according to local requirements.

2. Male or female in- or out-patient from 0 months (newborns) to <18 years on the dateof enrolment (Day 1).

3. Cohort 1: Patient < 6 months weighing at least 4 kg or patient ≥ 6 months weighingat least 6 kg. Cohort 2: Patient weighing at least 4 kg.

4. Patient with a predicted life expectancy ≥3 months according to Investigator'sopinion.

5. Patient naïve or non-naïve to chemotherapy, with histologically and/or cytologically (or imaging in the case of brain tumours and nephroblastomas) confirmed malignantdisease.

6. Cohort 1: Patient scheduled and eligible to receive at least 1 cycle of single-dayHEC. Cohort 2: Patient scheduled and eligible to receive at least 1 cycle of multi-dayHEC.

(For the level of emetogenicity of the chemotherapeutic agents, refer to the POGOJanuary 2021 guideline).

7. For patients aged ≥10 years: Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2.

8. For patient with known hepatic impairment: the patient may be enrolled provided theserum ALT and AST are ≤2.5 ULN, the total bilirubin is ≤1.5 ULN, and in theInvestigator's opinion the impairment is not expected to jeopardize the patient'ssafety during the study.

9. For patient with known renal impairment: the patient may be enrolled provided theestimated glomerular filtration rate (eGFR) is ≥70 mL/min/1.73m2 (≥50 mL/min/1.73m2for children <3 months old) (the eGFR should be calculated using the modifiedSchwartz equation) and in the Investigator's opinion the impairment is not expectedto jeopardize the patient's safety during the study.

10. For patient with known history or predisposition to cardiac abnormalities: as perthe Investigator's opinion, the history/predisposition should not jeopardizepatient's safety during the study.

11. Patient with non-clinically significant abnormal laboratory values or withclinically relevant abnormal laboratory values may be enrolled if in theInvestigator's opinion the patient's safety is not expected to be jeopardized.

12. Female patient shall: a) not have attained menarche yet or b) have attained menarcheand have a negative serum pregnancy test at the Screening Visit and a negative urinepregnancy test at Day 1.

13. Male or female fertile patient using reliable contraceptive measures. Such measures,for patient and sexual partner, include: implants, injectables, combined oralcontraceptives, intrauterine devices, vasectomized/sterilized partner, use of adouble barrier method, or sexual abstinence. The patient and his/her parent(s)/legalguardian must be counselled on the importance of avoiding pregnancy before andduring the study.

Exclusion Criteria:

1. The patient and/or parent(s)/legal guardian are expected by the Investigator to benon compliant with the study procedures.

2. Patient has received or is scheduled to receive total body irradiation; total nodalirradiation; upper abdomen radiotherapy; half or upper body irradiation; orradiotherapy of the cranium, craniospinal regions, head and neck, lower thoraxregion, or the pelvis within 1 week prior to study entry (Day 1) or within 120 hafter start of chemotherapy on Day 1 (Cohort 1 patients) or within 168 h (for Cohort 2 patients receiving the last IV NEPA on Day 3) or 216 h (for Cohort 2 patientsreceiving the last IV NEPA on Day 5) from start of chemotherapy on Day 1.

3. Known history of allergy to any component of the study treatments or othercontraindications to any NK1-RAs or 5-HT3-RAs.

4. Active infection.

5. Any illness or condition that, in the opinion of the Investigator, may poseunwarranted risks in administering the investigational product to the patient.

6. Uncontrolled medical condition (e.g., uncontrolled insulin-dependent diabetesmellitus).

7. Patient experiencing ongoing vomiting from any organic aetiology (including patientswith history of gastric outlet obstruction or intestinal obstruction due toadhesions or volvulus), or patient with hydrocephalus.

8. Patient who experienced any vomiting, retching, or nausea within 24 h prior to theadministration of the study treatment on Day 1 (Note: functional vomiting forinfants, which is normally seen during the first 3 months of life, is not to beconsidered as vomiting).

9. Patient who received any drug with potential antiemetic effect within 24 h prior toadministration of study treatment on Day 1, including but not limited to thefollowing:

• NK1-RAs (e.g., (fos)aprepitant or any other drug of this class)

• 5-HT3-RAs (e.g., ondansetron, granisetron, dolasetron, tropisetron, ramosetron)

• Benzamides (e.g., metoclopramide, alizapride)

• Phenothiazines (e.g., prochlorperazine, promethazine, perphenazine,fluphenazine, chlorpromazine, thiethylperazine)

• Benzodiazepines initiated 48 h prior to study treatment administration on Day 1or expected to be administered within the efficacy assessment period, exceptfor single doses of midazolam, temazepam, or triazolam

• Butyrophenones (e.g., droperidol, haloperidol)

• Anticholinergics (e.g., scopolamine, except the inhaled anticholinergics forrespiratory disorders e.g., ipratropium bromide)

• Antihistamines (e.g., diphenhydramine, cyclizine, hydroxyzine,chlorphenhyramine, dimenhydrinate, meclizine)

• Domperidone

• Mirtazapine

• Olanzapine

• Prescribed cannabinoids (e.g., tetrahydrocannabinol, nabilone)

• Over-the-counter (OTC) antiemetics, OTC cold medications, or OTC allergymedications

• Herbal preparations containing ephedra or ginger

10. Patient who received palonosetron within 1 week prior to administration of studytreatment on Day 1.

11. Patient receiving systemic corticosteroid therapy above 0.14mg/kg or >10 mg ofprednisone daily or equivalent. Exception: Dexamethasone for the prevention of CINV is permitted in association with the studytreatment (Test Treatment and Reference Treatment) as per standard of care andapplicable guidelines, provided its dosage is reduced by 50% in consideration ofknown interactions with various NK1 RAs, including fosaprepitant and fosnetupitant.

12. Patient aged <6 years who received any investigational drug (defined as a medicationwith no marketing authorization granted for any age or indication) within 90 daysprior to Day 1, or patient aged ≥6 years who received any investigational drugwithin 30 days prior to Day 1, or patient any age who is expected to receiveinvestigational drugs prior to study completion.

13. Intake of alcohol, food, or beverages (e.g., grapefruit, cranberry, pomegranate, andaloe vera juices; German chamomile) known to interfere with CYP3A4 or CYP2D6metabolic enzymes within 1 week prior to Day 1 and during the overall study period.

14. Use of any drugs or substances known to be strong inhibitors of CYP3A4 or CYP2D6enzymes within 1 week prior to Day 1 or planned to be used during the overall studyperiod.

15. Use of any drugs or substances known to be CYP3A4 substrates with narrow therapeuticrange within 1 week prior to Day 1 or planned to be used during the overall studyperiod.

16. Use of any drugs or substances known to be strong inducers of CYP3A4 or CYP2D6enzymes within 4 weeks prior to Day 1 or planned to be used during the overall studyperiod.

17. Lactating female patient.

18. Enrolment in a previous study on netupitant (either administered alone or incombination with palonosetron).

19. Marked baseline prolongation of QTc interval (QTcF>460 millisecond [msec]). At thediscretion of the investigator, criterion may be based on automatic interpretationof results.