PK/PD Study of Netupitant and Palonosetron in Pediatric Patients for Prevention of Chemotherapy-induced Nausea and Vomiting

This study is Phase 2 pharmacokinetic (PK) and pharmacodynamic (PD) dose-finding study of oral netupitant administered concomitantly with oral palonosetron in pediatric cancer patients for the prevention of nausea and vomiting associated with emetogenic chemotherapy. Two different netupitant dosages will be tested in patients aged from 3 months to \< 18 years: 1.33 mg/kg up to a maximum of 100 mg, and 4 mg/kg up to a maximum of 300 mg. All netupitant doses in all age classes will be concomitantly administered with palonosetron 20 μg/kg (up to a maximum dose of 1.5 mg) which is the IV palonosetron dose approved by USA FDA for the pediatric population. The primary objective is to investigate the PK/PD relationship between netupitant exposure (AUC, Cmax) and antiemetic efficacy (CR in delayed phase) after a single oral netupitant administration, concomitantly with oral palonosetron in pediatric cancer patients receiving Moderately Emetogenic Chemotherapy (MEC) or Highly Emetogenic Chemotherapy (HEC) cycles. Efficacy parameter to be used in the correlation is the proportion of patients with Complete Response (CR i.e., no emetic episodes and no rescue medication) during (\> 24-120 h after the start of chemotherapy on Day 1).

The secondary objectives are to assess the safety and tolerability after single oral administration of netupitant given concomitantly with a single oral administration of palonosetron; to evaluate the pharmacokinetic (AUC, Cmax, tmax and t1/2) of oral palonosetron at the fixed dose of 20 μg/kg in pediatric patients with the concomitant administration of netupitant. A total of 92 pediatric cancer patients receiving either HEC or MEC will be enrolled in the study.


Eligibility Criteria:
Inclusion Criteria:

1. Signed written informed consent 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.
2. Male or female in- or out-patient from birth to \< 18 years at the time of randomization.
3. Patient weight at least 3.3 kg.
4. Naïve or non-naïve patient with histologically, and/or cytologically (or imaging in the case of brain tumors) confirmed malignant disease.
5. Scheduled and eligible to receive at least one moderately or highly emetogenic chemotherapeutic agent on Day 1 only or for multiple days.
6. For patient aged ≥ 10 years: Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2.
7. For patient aged 2 years with known mild to moderate hepatic impairment: in the Investigator's opinion the impairment does not jeopardize patient's safety during the study.
8. For patient aged 2 years with known mild to moderate renal impairment: in the Investigator's opinion the impairment should not jeopardize patient's safety during the study.
9. For patient 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.
10. If the patient is female, she shall: a) not have attained menarche yet or b) have attained menarche and have a negative pregnancy test at the screening visit and at Day 1.
11. Male or female fertile patient using reliable contraceptive measures (such measures, for patient and sexual partner, include: implants, injectables, combined oral contraceptives, intrauterine devices, vasectomized/sterilized partner, use of a double-barrier method or sexual abstinence). The patient and his/her parent(s)/legal guardians must be counseled on the importance of avoiding pregnancy before or during the study.

Exclusion Criteria:

1. The patient and/or parents/caregivers are expected by the Investigator to be non-compliant with the study procedures.
2. Patient has received or is scheduled to receive total body irradiation, total nodal irradiation, upper abdomen radiotherapy, half or upper body irradiation, radiotherapy of the cranium, craniospinal regions, head and neck, lower thorax region or the pelvis within 1 week prior to study entry (Day 1) or within 120 h after start of chemotherapy administration on Day 1.
3. Known history of allergy to any component or other contraindications to any Neurokinin-1 (NK1) or 5-hydroxytryptamine 3 (5-HT3) receptor antagonists.
4. Active infection.
5. Uncontrolled medical condition (e.g., uncontrolled insulin dependent diabetes mellitus).
6. 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, patients with a symptomatic central nervous system(CNS) tumor causing nausea and/or vomiting) or patient with hydrocephalus.
7. Patient who experienced any vomiting, retching, or nausea within 24 h prior to the administration of the study drug
8. Patient who received any drug with potential anti-emetic effect within 24 h prior to the start of reference chemotherapy, including but not limited to:

   NK1- receptor antagonists (e.g., aprepitant or any other new drug of this class); 5-HT3 receptor antagonists (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 drug administration or expected to be received within 120 h following initiation of chemotherapy, except for single doses of midazolam, temazepam or triazolam; Butyrophenones (e.g., droperidol, haloperidol); Anticholinergics (e.g., scopolamine, with the exception of inhaled anticholinergics for respiratory disorders e.g., ipratropium bromide); Antihistamines (e.g., diphenhydramine, cyclizine, hydroxyzine, chlorpheniramine, dimenhydrinate, meclizine); Domperidone; Mirtazapine; Olanzapine; Prescribed cannabinoids (e.g., tetrahydrocannabinol, nabilone); Over the Counter (OTC) antiemetics, OTC cold or OTC allergy medications; Herbal preparations containing ephedra or ginger.
9. Patient who received palonosetron within 1 week prior to administration of study drug.
10. Patient who has been started on systemic corticosteroid therapy within 72 h prior to study drug administration or is planned to receive a corticosteroid as part of the chemotherapy regimen
11. Patient aged \< 6 years who received any investigational drug (defined as a medication with no marketing authorization granted for any age class 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.
12. Intake of alcohol, food or beverages (e.g., grapefruit, cranberry, pomegranate and aloe vera juices, German chamomile) known to interfere with either CYP3A4 or CYP2D6 metabolic enzymes within 1 week prior to Day 1 and during the overall study period.
13. Use of any drugs or substances known to be strong or moderate inhibitors of CYP3A4 and CYP2D6 enzymes within 1 week prior to Day 1 or planned to be used during the overall study period.
14. Use of any drugs or substances known to be CYP3A4 substrates with narrow therapeutic range within 1 week prior to Day 1, or planned to be used during the overall study period.
15. Use of any drugs or substances known to be inducers of CYP3A4 enzymes within 4 weeks prior to Day 1 or planned to be used during the overall study period.
16. Lactating female patient.
17. Patient with clinically relevant abnormal laboratory values that in the Investigator's opinion jeopardize the patient's safety during the study.
18. Patient aged \< 2 years with known hepatic impairment (any grade), or patient aged 2 years with known severe hepatic impairment.
19. Patient aged \< 2 years with known renal impairment (any grade), or patient aged 2 years with known severe renal impairment.
20. Enrolment in a previous study with netupitant (either alone or in combination with palonosetron).