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.

Study Overview

• Status: Completed
• Conditions: Chemotherapy-Induced Nausea and Vomiting
• Intervention / Treatment: Drug: Palonosetron; Drug: Palonosetron; Drug: Placebo to Ondansetron; Drug: Ondansetron; Drug: Placebo to Palonosetron

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 502
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1431FWO
    • CEMIC
  • Buenos Aires, Argentina, C1181ACH
    • Hospital Italiano de Buenos Aires
  • Cordoba, Argentina, X5016KEH
    • Hospital Privado Centro Medico de Cordoba
  • El Palomar, Argentina, 1684
    • Hospital Nacional "Prof. Dr. Alejandro Posadas"
• Austria
  • Wien, Austria, 1090
    • Medical University of Vienna
  • Wien, Austria, 1090
    • Children's Cancer Research Institute
• Bulgaria
  • Plovdiv, Bulgaria, 4002
    • Pediatrics and Genetic Medicine Clinic
  • Sofia, Bulgaria, 1527
    • Specialised Hospital for Active Treatment of Oncohematological Diseases in Children
  • Varna, Bulgaria, 9010
    • Specialised Pediatric Clinic of Clinical Hematology and Oncology Mutiprofile Hospital for Active Treatment "Sveta Marina"
• Chile
  • Santiago, Chile, 8431657
    • Clínica Dávila
  • Santiago, Chile, 8330024
    • Hospital Clinico UC
  • Santiago, Chile, 750053
    • Hospital Dr Luis Calvo Mackenna
  • Santiago, Chile, 7520378
    • Clinica Santa Maria SA
• Czech Republic
  • Brno, Czech Republic, 625 00
    • University Hospital Brno, Children's Medical Centre, Clinic of Pediatric Oncology
  • Ostrava, Czech Republic, 708 52
    • University Hospital in Ostrava, Clinic of Pediatric
  • Plzen-Lochotin, Czech Republic, 304 60
    • University Hospital in Pilsen
  • Praha 5, Czech Republic, 150 06
    • University Hospital Motol, Department of Paediatric Heamatology and Oncology
• Estonia
  • Tallinn, Estonia, 13419
    • Tallin Children's Hospital
  • Tartu, Estonia, 51014
    • Tartu University Hospital, Hematology - Oncology Clinic
• France
  • Lille Cedex, France, 59037
    • CHRU de Lille - Hopital d'Hematologie Pediatrique
  • Montpellier, France, 34295
    • Hopital Arnaud de Villenueve
  • Tours Cedex 09, France, 37044
    • CHRU de Tours - Centre de Pediatrie Gatien de Clocheville
• Germany
  • Cologne, Germany, 50924
    • University Hospital of Cologne
  • Freiburg, Germany, 79106
    • University Medical Center Freiburg
• Hungary
  • Budapest, Hungary, H-1094
    • Semmelweis University, 2nd Department of Pediatrics
  • Szeged, Hungary, H-6720
    • University of Szeged, Szent-Gyorgyl Albert Clinical Center, Department of Pediatrics
• Peru
  • Lima, Peru, 34
    • Instituto Nacional de Enfermedades Neoplasicas
  • Lima, Peru, Lima 41
    • Oncosalud SAC RCI 300
  • San Isidro Lima, Peru, 27
    • Clinica Anglo Americana - Centro de Investigacion Oncologica CAA
• Poland
  • Bydgoszcz, Poland, 85-094
    • Szpital Uniwersytecki - Department of Pediatrics, Hematology and Oncology
  • Gdansk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne
  • Lodz, Poland, 91-378
    • Samodzielny Publiczny Zaklad Opieki Zdrowotnej Uniwersytecki Szpital
  • Lublin, Poland, 20-093
    • Dzieciecy Szpital Kliniczny
  • Warsaw, Poland, 04-730
    • Institut Pomnik - The Children Memorial Health Institute, Department of Oncology
  • Wroclaw, Poland, 50-368
    • Samodzielny Publiczny Szpital
• Romania
  • Bucharest, Romania, 022328
    • Fundeni Clinical Institute, Pediatrics Clinic
  • Bucharest, Romania, 022338
    • "Prof. Dr. Alexandru Trestioreanu" Institute of Oncology, Pediatric Oncology Department
  • Cluj, Romania, 400015
    • "Prof. Dr. Ion Chiricuta" Institute of Oncology, Cluj-Napoca Pediatric Department
  • Iasi, Romania, 700309
    • Sf. Maria - Chidren's Emergency Clinical Hospital
• Russian Federation
  • Chelyabinsk, Russian Federation, 454076
    • Chelyabinsk Pediatric Regional Clinical Hospital, Oncohematology Department
  • Ekaterinburg, Russian Federation, 620149
    • Regional Pediatric Clinical Hospital #1
  • Krasnodar, Russian Federation, 350007
    • Pediatric Regional Clinical Hospital
  • Moscow, Russian Federation, 115478
    • Russian Oncology Research Center
  • Moscow, Russian Federation, 119049
    • Moscow State Institution: Morozovskaya Pediatric City Clinical Hospital
  • Omsk, Russian Federation, 644013
    • Omsk Regional Clinical Oncology Center
  • St. Petersburg, Russian Federation, 197022
    • St. Petersburg State Medical University
  • St. Petersburg, Russian Federation, 197110
    • State Clinical Hospital
• Serbia
  • Belgrade, Serbia, 11000
    • Department for hematology and oncology
  • Nis, Serbia, 18000
    • Clinical Center Nis, Clinic for pediatrics internal diseases, Department for hematology and oncology
• Ukraine
  • Donetsk, Ukraine, 83045
    • State Institution: V. K. Husak Institute of Urgent and Reconstructive Surgery
  • Donetsk, Ukraine, 83052
    • Public Treatment and Prophylaxis Institution: Regional Children's Clinical Hospital
  • Kharkiv, Ukraine, 61051
    • Public Healthcare Institution: Regional Children's Clinical Hospital #1
  • Kyiv, Ukraine, 03022
    • National Institute of Cancer
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • A. I. Dupont Hospital For Children
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Orlando, Florida, United States, 32806
      • Nemours Children's Clinic-Orlando
    • Pensacola, Florida, United States, 32504
      • Nemours Children's Clinic
  • Georgia
    • Savannah, Georgia, United States, 31404
      • Backus Children's Hospital at University Pediatrics
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky - Chandler Medical Center
  • New York
    • Syracuse, New York, United States, 13210
      • Upstate Medical University
    • Valhalla, New York, United States, 10595
      • Department of Pediatrics
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 16 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Palonosetron 10 mcg/kg; Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron	Drug: Palonosetron; Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg; Drug: Palonosetron; Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg; Drug: Placebo to Ondansetron
EXPERIMENTAL: Palonosetron 20 mcg/kg; Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron	Drug: Palonosetron; Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg; Drug: Palonosetron; Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg; Drug: Placebo to Ondansetron
ACTIVE_COMPARATOR: Ondansetron; Ondansetron and placebo to Palonosetron Drug: Comparator: Ondansetron	Drug: Ondansetron; Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg; Drug: Placebo to Palonosetron

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With Complete Response 0 to 24 Hours (Acute Phase) in Cycle 1	Complete Response (CR) was defined as no vomiting, no retching, and no use of antiemetic rescue medication from 0 to 24 hours (acute phase) after T0 (start of administration of the most emetogenic chemotherapy) during first cycle. Time 0 (T0) is defined as the time when the patient starts the first cycle of chemotherapy.	0 to 24 hours after T0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With Complete Response >24 to 120 Hours (Delayed Phase) in Cycle 1	Complete Response (CR) was defined as no vomiting, no retching, and no use of antiemetic rescue medication from >24 to 120 hours (delayed phase) after T0 (start of administration of the most emetogenic chemotherapy) during first cycle.	from >24 to 120 hours (delayed phase) after T0

Collaborators and Investigators

• Sponsor: Helsinn Healthcare SA

Publications and helpful links

General Publications

• Kovacs G, Wachtel AE, Basharova EV, Spinelli T, Nicolas P, Kabickova E. Palonosetron versus ondansetron for prevention of chemotherapy-induced nausea and vomiting in paediatric patients with cancer receiving moderately or highly emetogenic chemotherapy: a randomised, phase 3, double-blind, double-dummy, non-inferiority study. Lancet Oncol. 2016 Mar;17(3):332-344. doi: 10.1016/S1470-2045(15)00520-3. Epub 2016 Jan 19.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (ACTUAL): October 1, 2012
• Study Completion (ACTUAL): November 1, 2012

Study Registration Dates

• First Submitted: September 21, 2011
• First Submitted That Met QC Criteria: September 27, 2011
• First Posted (ESTIMATE): September 28, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): August 7, 2014
• Last Update Submitted That Met QC Criteria: August 4, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Pediatric; Ondansetron; Palonosetron; Prevention of Chemotherapy-Induced Nausea and Vomiting
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Nausea; Vomiting; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Serotonin Antagonists; Anti-Anxiety Agents; Serotonin 5-HT3 Receptor Antagonists; Antipruritics; Palonosetron; Ondansetron
• Other Study ID Numbers: PALO-10-20