Efficacy and Safety of Palonosetron Intravenous in Prevention of Chemotherapy Induced Nausea and Vomiting in Pediatric Patients

A Multicenter, Randomized, Double-blind, Parallel Group Study to Evaluate the Efficacy and Safety of Two Different Doses of Palonosetron Compared to Ondansetron in the Prevention of CINV in Pediatric Patients Undergoing Single and Repeated Cycles of MEC or HEC

The primary objective is to evaluate the efficacy of two different doses of IV palonosetron in the prevention of chemotherapy induced nausea and vomiting in MEC and HEC patients through 120 hours after start of chemotherapy in single and repeated chemotherapy cycles. The secondary objectives are to evaluate the safety and tolerability of IV palonosetron in pediatric patients and evaluate the pharmacokinetics of IV palonosetron in a subset of pediatric CINV patients.

For neonates (<28 days, full term) an open-label sub-study will be conducted to assess exposure and tolerability in this age group with escalating doses of palonosetron, starting with 3 mcg/kg to the first three or more neonates included in the study. If this dose is shown to be safe and well tolerated then the following three neonates will be treated with a dose of 10 mcg/kg. If also this dose is safe and well tolerated, then the following three neonates will be treated with a dose of 20 mcg/kg. If this last dose is also shown to be safe and well tolerated, then all the following neonates will be randomized to the main study.

Inclusion Criteria:

• Written informed consent signed by parent(s)/legal guardians of the pediatric patient in compliance with the local laws and regulations. In addition signed children's assent form according to local requirements
• Male or female in- or out-patients from neonates (full term) to <17 years at the time of randomization
• Patient weight at least 3.2 kg
• Histologically, and/or cytologically (or imaging in the case of brain tumors) confirmed malignant disease
• Naïve or non-naïve to chemotherapy
• Scheduled and eligible to receive at least one of the moderately or highly emetogenic chemotherapeutic agents on Study Day 1
• For patients aged ≥ 10 years to <17 years: ECOG PS ≤ 2
• For patients with known hepatic impairment: in the Investigator's opinion the impairment should not jeopardize patient's safety during the study
• For patients with known renal impairment: in the Investigator's opinion the impairment should not jeopardize patient's safety during the study
• For patients with known history or predisposition to cardiac abnormalities: in the Investigator's opinion the history/predisposition should not jeopardize patient's safety during the study
• For patients with known clinically relevant abnormal laboratory values: in the Investigator's opinion the abnormality should not jeopardize the patient's safety during the study
• Fertile patients (male or female) must use reliable contraceptive measures
• Female patients who have attained menarche must have a negative pregnancy test at the screening visit (Visit 1) and at study treatment visit (Visit 2)

Exclusion Criteria:

• Lactating or pregnant female patient
• Patient has received total body irradiation, upper abdomen radiotherapy, radiotherapy of the cranium, craniospinal regions or the pelvis within 1 week prior to study entry (screening)
• Scheduled to receive concomitant total body irradiation, radiotherapy of the upper abdomen, lower thorax region, or cranium/craniospinal regions up to 24 hours after study drug administration
• Known history of allergy to any component or other contraindications to any 5-HT3 receptor antagonists
• Active infection
• Uncontrolled medical condition
• Marked baseline prolongation of QTc interval [QTcB or QTcF > 460 msec] in any of the ECG assessments at screening. For this purpose, assessment will rely on the automatic interpretation by the ECG machine
• Patient suffering from ongoing vomiting from any organic etiology (including patients with history of gastric outlet obstruction or intestinal obstruction due to adhesions or volvulus) or patients with hydrocephalus
• Patient who experienced any vomiting, retching, or nausea within 24 hours prior to the administration of the study drug
• Patient who received any drug with potential anti-emetic effect within 24 hours prior to administration of study treatment, including but not limited to:
• NK1- receptor antagonists (e.g. aprepitant)
• 5-HT3 antagonists (e.g., ondansetron, granisetron, dolasetron);
• Phenothiazines (e.g., perphenazine, prochlorperazine, promethazine, fluphenazine, chlorpromazine, thiethylperazine);
• Butyrophenones (e.g., droperidol, haloperidol);
• Benzamides (e.g., metoclopramide, alizapride);
• Corticosteroids (e.g., prednisone, methylprednisolone; except inhaled steroids for respiratory disorders and topical steroids for skin disease with doses of ≤ 10 mg of prednisone daily or its equivalent); Corticosteroids foreseen in the chemotherapy regimen or to reduce intracranial pressure are allowed. According to the guidelines1,2, patients will receive also dexamethasone as a co-medication in accordance with standard clinical practice and if deemed appropriate by the Investigator.
• Dimenhydrinate; Hydroxyzine; Domperidone; Lorazepam; Cyclizine; Cannabinoids; Scopolamine; Trimethobenzamide HCl; Meclizine hydrochloride; Pseudoephedrine HCl;
• Over the Counter (OTC) antiemetics, OTC cold or OTC allergy medications;
• Herbal preparations containing ephedra or ginger.
• Patient aged ≤ 6 years who received any investigational drug (defined as a medication with no marketing authorization granted for any age group and any indication) within 90 days prior to Day 1, or patient aged > 6 years who received any investigational drug within 30 days prior to Day 1 or is expected to receive investigational drugs prior to study completion
• Patient who participated in any previous trial with palonosetron