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

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ClinicalTrials.gov Identifier: NCT03204279
Recruitment Status : Recruiting
First Posted : July 2, 2017
Last Update Posted : October 17, 2018
Sponsor:
Information provided by (Responsible Party):
Helsinn Healthcare SA

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Chemotherapy-induced Nausea and Vomiting (CINV) Drug: Netupitant Drug: Palonosetron Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 92 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: A Multicenter Multinational Randomized Double Blind PK/PD Dose-finding Study of Oral Netupitant Given With Oral Palonosetron in Pediatric Cancer Patients for Prevention of Nausea and Vomiting Associated With Emetogenic Chemotherapy
Actual Study Start Date : August 31, 2017
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Netupitant 1.33 mg/kg plus Palonosetron
Single oral dose of Netupitant 1.33 mg/kg up to a maximum of 100 mg (for patients < 3 months of age the netupitant dose will be 0.8 mg/kg) administered with single oral dose of 20 μg/kg palonosetron up to a maximum of 1.5 mg.
Drug: Netupitant
Netupitant 1.33 mg/kg oral suspension up to a maximum of 100 mg

Drug: Palonosetron
Palonosetron 20 μg/kg solution for oral use up to a maximum of 1.5 mg

Experimental: Netupitant 4 mg/kg plus Palonosetron
Single oral dose of Netupitant 4 mg/kg up to a maximum of 300 mg (for patients < 3 months of age the netupitant dose will be 2.4 mg/kg) administered with single oral dose 20 μg/kg palonosetron up to a maximum of 1.5 mg.
Drug: Netupitant
Netupitant 4 mg/kg oral suspension up to a maximum of 300 mg

Drug: Palonosetron
Palonosetron 20 μg/kg solution for oral use up to a maximum of 1.5 mg




Primary Outcome Measures :
  1. Area Under the plasma Concentration versus time curve from time zero to infinity (AUC) of netupitant [ Time Frame: within 168 hours after netupitant administration. A sampling windows approach will be used by collecting a single blood sample from each patient in one of these time windows: from 2 to 8 h, from 24 to 48 h, from 72 to 96 h and from 120 to 168 h ]
    Area Under the plasma Concentration versus time curve from time zero to infinity (AUC) of netupitant after a single oral netupitant administration, concomitantly with oral palonosetron, in pediatric cancer patients receiving HEC or MEC cycles. AUC estimates are obtained by non-compartmental analysis of population model-predicted individual plasma concentration-time profiles.

  2. Maximum plasma concentration (Cmax) of netupitant [ Time Frame: within 168 hours after netupitant administration. A sampling windows approach will be used by collecting a single blood sample from each patient in one of these time windows: from 2 to 8 h, from 24 to 48 h, from 72 to 96 h and from 120 to 168 h ]
    Maximum plasma concentration (Cmax) of netupitant after a single oral netupitant administration, concomitantly with oral palonosetron, in pediatric cancer patients receiving HEC or MEC cycles. Cmax estimates are obtained by non-compartmental analysis of population model-predicted individual plasma concentration-time profiles

  3. Proportion of pediatric patients with complete response during the delayed phase [ Time Frame: > 24-120 hours after the start of chemotherapy on Day 1 ]
    Proportion of pediatric patients with complete response (CR, i.e., no emetic episodes and no rescue medication) during the delayed phase (> 24 to 120 h after the start of chemotherapy on Day 1) after a single oral netupitant administration, concomitantly with oral palonosetron, in pediatric cancer patients receiving HEC or MEC cycles.

  4. Exposure - Response analysis for netupitant [ Time Frame: > 24-120 hours after the start of chemotherapy on Day 1 ]
    Exposure - Response analysis for netupitant performed by assessing the relationships between exposure parameters AUC and Cmax with the primary efficacy endpoint, i.e., the CR in the delayed phase



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03204279


Contacts
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Contact: Anastasia Eremeeva, MD +7 812 320 38 55 ext 0334 Anastasia.Eremeeva@psi-cro.com

Locations
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United States, Delaware
Nemours/A.I. duPont Hospital for Children Recruiting
Wilmington, Delaware, United States, 19803
Contact: Emi Caywood, MD    302-651-5500    ecaywood@nemours.org   
United States, Florida
Nemours Children's Clinic Recruiting
Jacksonville, Florida, United States, 32207
Contact: Manisha Bansal, MD    904-697-3896    mbansal@nemours.org   
Nemours Children's Hospital - Orlando Recruiting
Orlando, Florida, United States, 32827
Contact: Ramamoorthy Nagasubramanian, MD    407-650-7652    rnagasub@nemours.org   
United States, Maine
Maine Medical Center - Cancer Medicine and Blood Disorders - Scarborough Recruiting
Scarborough, Maine, United States, 04074
Contact: Stanley Chaleff, MD    207-885-7565    Chales1@mmc.org   
United States, South Carolina
Medical University of South Carolina Recruiting
Charleston, South Carolina, United States, 29425
Contact: Jacqueline Kraveka, MD    843-792-2957    kravekjm@musc.edu   
Russian Federation
Chelyabinsk Regional Children's Clinical Hospital Recruiting
Chelyabinsk, Russian Federation
Contact: Elena Basharova, Dr    +7 (351) 261 1371    lbasharova@mail.ru   
Children's Territorial Clinical Hospital Recruiting
Krasnodar, Russian Federation
Contact: Mikhail Melnikov, Dr.    +7 (861) 268 5214    kkdkb@mail.ru   
Dmitry Rogachev National Scientific and Practical Center for Pediatric Hematology, Oncology and Immunology Recruiting
Moscow, Russian Federation
Contact: Alexey Maschan, Prof.    +7 (495) 936 9169    amaschan@mail.ru   
City Clinical Hospital #31 Recruiting
St. Petersburg, Russian Federation
Contact: Margarita Belogurova, Prof.    +7 (812) 235 0721    deton.hospital31@inbox.ru   
First I.P. Pavlov State Medical University of St. Petersburg Recruiting
St. Petersburg, Russian Federation
Contact: Lyudmila Zubarovskaya, Dr.    +7 (812) 233 4473    zubarovskaya_ls@mail.ru   
Voronezh Regional Children's Cinical Hospital #1 Recruiting
Voronezh, Russian Federation, 394024
Contact: Natalia B Yudina, MD    7 (910) 732 14 21    n.yudina@list.ru   
Regional Children's Clinical Hospital #1 Recruiting
Yekaterinburg, Russian Federation
Contact: Oleg Arakaev, Dr    +8 (343) 216 68 97    olegarakaev@gmail.com   
Serbia
University Children's Hospital, Center for Pediatrics, Department of Hematology and Oncology Recruiting
Belgrade, Serbia
Contact: Dragana Janic, Dr.    +381 (11) 206 0691    drjanic@eunet.rs   
Clinical Center Nis, Clinic of Pediatric Internal Diseases Recruiting
Nis, Serbia
Contact: Vesna Bogicevic, Dr.    +381 (64) 181 0880    vajav@mts.rs   
Ukraine
Dnipropetrovsk Regional Children's Clinical Hospital Recruiting
Dnipro, Ukraine, 49100
Contact: Natalia A. Dementieva, MD    +380 (56) 713 7100    dementievana@ukr.net; k7-dodkb@yandex.ru   
National Institute of Cancer, Research Department of Pediatric Oncology Recruiting
Kyiv, Ukraine
Contact: Hryhorii Klymniuk, MD    +380 (44) 259 0185    gklymnyuk@gmail.com   
West Ukrainian Specialized Children's Medical Center, Department of Pediatric Surgery Recruiting
Lviv, Ukraine
Contact: Zoriana Kizyma, MD    +380 (322) 702 079    zoryanakizyma@gmail.com   
Sponsors and Collaborators
Helsinn Healthcare SA

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Responsible Party: Helsinn Healthcare SA
ClinicalTrials.gov Identifier: NCT03204279     History of Changes
Other Study ID Numbers: NEPA-15-31
First Posted: July 2, 2017    Key Record Dates
Last Update Posted: October 17, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Nausea
Vomiting
Signs and Symptoms, Digestive
Signs and Symptoms
Palonosetron
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Serotonin 5-HT3 Receptor Antagonists
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action