A Study of MK-0869 (Aprepitant) and MK-0517 (Fosaprepitant) in Pediatric Participants Receiving Chemotherapy (MK-0869-134)

A Multicenter, Open-Label, 5-Part Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Aprepitant and Fosaprepitant Dimeglumine in Pediatric Patients Receiving Emetogenic Chemotherapy

This study will determine the appropriate dosing regimen of aprepitant and fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in pediatric participants from 0 months to 17 years of age.

Study Overview

• Status: Terminated
• Conditions: Chemotherapy-Induced Nausea and Vomiting
• Intervention / Treatment: Drug: Experimental: aprepitant; Drug: Experimental: fosaprepitant; Drug: Ondansetron; Drug: Dexamethasone; Drug: Comparator: ondansetron

Detailed Description

Fosaprepitant is a prodrug for aprepitant and is rapidly converted to aprepitant after intravenous administration; the pharmacological effect of fosaprepitant is attributed to aprepitant. The birth to one year old cohort will be initiated in Parts III and IV upon completion of Part II (Steps A and B) in participants <6 months of age.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Is 0 (at least 37 weeks gestation) to 17 years of age
• Is scheduled to receive moderately to highly nausea-inducing chemotherapy or participant did not tolerate a previous chemotherapy regimen that is planned to be repeated
• Is expected to receive ondansetron
• Female participants who have begun menstruating must have a negative pregnancy test
• Weighs ≥3.0 kg if <6 months of age, ≥6.0 kg if >6 months of age, and ≥7.5 kg if > 2 years of age
• Has a pre-existing venous catheter

Exclusion Criteria:

• Uses any illicit drugs or abuses alcohol
• Is pregnant or breast feeding
• Has a symptomatic central nervous system (CNS) tumor
• Has an infection or other uncontrolled disease other than cancer
• Has known history of heart QT wave prolongation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part IA-fosaprepitant 115 mg/aprepitant; Day 1, fosaprepitant intravenous (IV) at a dose of 115 mg and Days 2 and 3, aprepitant 80 mg orally (PO), prior to chemotherapy for participants from 12 to 17 years of age. Participants also receive ondansetron IV as per local standard of care, with or without dexamethasone IV.	Drug: Experimental: aprepitant; aprepitant powder for suspension, 125 mg/sachet, PO; Other Names: Emend; MK-0869; Drug: Experimental: fosaprepitant; fosaprepitant lyophilized powder for suspension, 115 mg/vial or 150 mg/vial, IV; Other Names: MK-0517; Emend injection; Fosaprepitant Dimeglumine; Drug: Ondansetron; ondansetron solution for infusion, IV, administered per local standard of care; Drug: Dexamethasone; dexamethasone solution for infusion, IV, administered per local standard of care
Experimental: Part IB-fosaprepitant 150 mg; Day 1, fosaprepitant, IV at a dose of 150 mg, prior to chemotherapy for participants 12 to 17 years of age. Participants also receive ondansetron IV as per local standard of care, with or without dexamethasone IV.	Drug: Experimental: fosaprepitant; fosaprepitant lyophilized powder for suspension, 115 mg/vial or 150 mg/vial, IV; Other Names: MK-0517; Emend injection; Fosaprepitant Dimeglumine; Drug: Ondansetron; ondansetron solution for infusion, IV, administered per local standard of care; Drug: Dexamethasone; dexamethasone solution for infusion, IV, administered per local standard of care
Experimental: Part IIA-aprepitant 80 mg equiv.; Day 1, aprepitant PO prior to chemotherapy at the dosing regimens listed for the following age ranges: 6 months to <12 years of age - 47 mg/m^2; 4 months to <6 months of age - 2.0 mg/kg; 1 month to <4 months of age - 1.0 mg/kg; birth to <1 month of age - 0.5 mg/kg. Participants also receive ondansetron IV as per local standard of care, with or without dexamethasone IV.	Drug: Experimental: aprepitant; aprepitant powder for suspension, 125 mg/sachet, PO; Other Names: Emend; MK-0869; Drug: Ondansetron; ondansetron solution for infusion, IV, administered per local standard of care; Drug: Dexamethasone; dexamethasone solution for infusion, IV, administered per local standard of care
Experimental: Part IIB-aprepitant 125 mg equiv.; Day 1, aprepitant PO prior to chemotherapy at the dosing regimens listed for the following age ranges: 2 years to <12 years of age - 74 mg/m^2; 6 months to <2 years of age - 1.3 mg/kg; 4 months to <6 months of age - 3.0 mg/kg; 1 month to <4 months of age - 1.5 mg/kg; birth to <1 month of age - 0.75 mg/kg. Participants also receive ondansetron IV as per local standard of care, with or without dexamethasone IV.	Drug: Experimental: aprepitant; aprepitant powder for suspension, 125 mg/sachet, PO; Other Names: Emend; MK-0869; Drug: Ondansetron; ondansetron solution for infusion, IV, administered per local standard of care; Drug: Dexamethasone; dexamethasone solution for infusion, IV, administered per local standard of care
Active Comparator: Part III-ondansetron; Ondansetron administered IV per local standard of care on Days 1, 2, and 3 prior to chemotherapy for participants from birth to <12 years of age. The use of IV dexamethasone is optional with the exception of the birth to one year old cohort.	Drug: Dexamethasone; dexamethasone solution for infusion, IV, administered per local standard of care; Drug: Comparator: ondansetron; ondansetron solution for infusion, IV, administered per local standard of care; Other Names: Zofran
Experimental: Part IV-aprepitant regimen; Day 1, aprepitant, PO, prior to chemotherapy at the dosing regimens listed for the following age ranges: 4 months to <12 years of age - 3.0 mg/kg; 1 month to <4 months of age - 1.5 mg/kg; Birth to <1 month of age - 0.75 mg/kg; Days 2 and 3, aprepitant, PO, prior to chemotherapy at the dosing regimens listed for the following age ranges: 4 months to <12 years of age - 2.0 mg/kg; 1 month to <4 months of age - 1.0 mg/kg; Birth to <1 month of age - 0.5 mg/kg. Participants also receive ondansetron IV as per local standard of care. The use of dexamethasone IV is optional with the exception of the birth to one year old cohort.	Drug: Experimental: aprepitant; aprepitant powder for suspension, 125 mg/sachet, PO; Other Names: Emend; MK-0869; Drug: Ondansetron; ondansetron solution for infusion, IV, administered per local standard of care; Drug: Dexamethasone; dexamethasone solution for infusion, IV, administered per local standard of care
Experimental: Part V-fosaprepitant regimen; Day 1, fosaprepitant, IV at a dose of 3 mg/kg prior to chemotherapy for participants 6 months to <12 years of age. Participants also receive ondansetron IV as per local standard of care, with or without dexamethasone IV.	Drug: Experimental: fosaprepitant; fosaprepitant lyophilized powder for suspension, 115 mg/vial or 150 mg/vial, IV; Other Names: MK-0517; Emend injection; Fosaprepitant Dimeglumine; Drug: Ondansetron; ondansetron solution for infusion, IV, administered per local standard of care; Drug: Dexamethasone; dexamethasone solution for infusion, IV, administered per local standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Time-Concentration Curve From 0 to 24 Hours (AUC 0-24hr) for Aprepitant	AUC is a measure of the amount of aprepitant in the plasma. Fosaprepitant is a prodrug for aprepitant and is rapidly converted to aprepitant after IV administration. Blood samples for pharmacokinetic (PK) assessment were collected at the following time points: Part IA - Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8 and 24 hours (hr) post fosaprepitant dose; Part IB - Pre-dose and -0.75, -0.5, 0, 0.5, 1.5, 3, 4, 6, 8 and 24 hr post start of chemotherapy; Parts II and IV - Pre-dose and 1.5, 3, 4, 6, 8 and 24 hr post aprepitant dose; Part V - Pre-dose and -0.75, -0.5, 0, 1.5, 3, 4, 6, 8 and 24 hr post start of chemotherapy.	Up to 24 hours post fosaprepitant/aprepitant dose
Maximum Plasma Concentration (Cmax) for Aprepitant	Cmax is a measure of the maximum amount of aprepitant in the plasma. Fosaprepitant is a prodrug for aprepitant and is rapidly converted to aprepitant after IV administration. Blood samples for PK assessment were collected at the following time points: Part IA - Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8 and 24 hr post fosaprepitant dose; Part IB - Pre-dose and -0.75, -0.5, 0, 0.5, 1.5, 3, 4, 6, 8, 24, 48 and 72 hr post start of chemotherapy; Parts II and IV - Pre-dose and 1.5, 3, 4, 6, 8, 24, 48 and 72 hr post aprepitant dose; Part V - Pre-dose and -0.75, -0.5, 0, 1.5, 3, 4, 6, 8, 24, 48 and 72 hr post start of chemotherapy.	Up to 72 hours post fosaprepitant/aprepitant dose
Time to Cmax (Tmax) for Aprepitant	Tmax is a measure of the amount of time after dosing to when the maximum concentration of aprepitant was achieved. Fosaprepitant is a prodrug for aprepitant and is rapidly converted to aprepitant after IV administration. Blood samples for PK assessment were collected at the following time points: Part IA - Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8 and 24 hr post fosaprepitant dose; Part IB - Pre-dose and -0.75, -0.5, 0, 0.5, 1.5, 3, 4, 6, 8, 24, 48 and 72 hr post start of chemotherapy; Parts II and IV - Pre-dose and 1.5, 3, 4, 6, 8, 24, 48 and 72 hr post aprepitant dose; Part V - Pre-dose and -0.75, -0.5, 0, 1.5, 3, 4, 6, 8, 24, 48 and 72 hr post start of chemotherapy.	Up to 72 hours post fosaprepitant/aprepitant dose
Apparent Terminal Half-life (t1/2) for Aprepitant	t1/2 is the amount of time from dosing until half of the aprepitant was metabolized from the body. Fosaprepitant is a prodrug for aprepitant and is rapidly converted to aprepitant after IV administration. Blood samples for PK assessment were collected at the following time points: Part IA - Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8 and 24 hr post fosaprepitant dose; Part IB - Pre-dose and -0.75, -0.5, 0, 0.5, 1.5, 3, 4, 6, 8, 24, 48 and 72 hr post start of chemotherapy; Parts II and IV - Pre-dose and 1.5, 3, 4, 6, 8, 24, 48 and 72 hr post aprepitant dose; Part V - Pre-dose and -0.75, -0.5, 0, 1.5, 3, 4, 6, 8, 24, 48 and 72 hr post start of chemotherapy.	Up to 72 hours post fosaprepitant/aprepitant dose
Cmax for Fosaprepitant	Cmax is a measure of the maximum amount of fosaprepitant in the plasma. Blood samples for PK assessment were collected at the following time points: Part IA - Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8 and 24 hr post fosaprepitant dose; Part V - Pre-dose and -0.75, -0.5, 0, 0.5, 1.5, 3, 4, 6, 8, 24, 48 and 72 hr post start of chemotherapy.	Up to 72 hours post fosaprepitant dose
Tmax for Fosaprepitant	Tmax is a measure of the amount of time after dosing to when the maximum concentration of fosaprepitant was achieved. Blood samples for PK assessment were collected at the following time points: Part IA - Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8 and 24 hr post fosaprepitant dose; Part V - Pre-dose and -0.75, -0.5, 0, 0.5, 1.5, 3, 4, 6, 8, 24, 48 and 72 hr post start of chemotherapy.	Up to 72 hours post fosaprepitant dose
Number of Participants Experiencing Adverse Events (AEs)	An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Participants were monitored for the occurrence AEs for up to 14 days after last dose of study drug.	Up to 14 days after last dose of study drug (Up to 17 days)
Number of Participants Discontinuing Study Drug Due to an AE	An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. The number of participants who discontinued from the study due to an AE are summarized.	Day 1 up to Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Concentration and PK Parameters of Dexamethasone in Participants From Birth to 1 Year of Age	Blood samples for PK assessment were to be collected at the following time points: Parts II and V - Pre-dose and 1.5, 3, 4, 6, 8 and 24 hr post start of chemotherapy; Parts III and IV - Immediately after infusion of dexamethsone and 0.5, 1.5, 3, 8 and 24 hr post start of chemotherapy.	Up to 24 hours post dexamethasone dose

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):385-94. doi: 10.1016/S1470-2045(15)70061-6. Epub 2015 Mar 12. Erratum In: Lancet Oncol. 2015 Sep;16(9):e427.

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2009
• Primary Completion (Actual): January 20, 2014
• Study Completion (Actual): January 20, 2014

Study Registration Dates

• First Submitted: January 6, 2009
• First Submitted That Met QC Criteria: January 6, 2009
• First Posted (Estimate): January 7, 2009

Study Record Updates

• Last Update Posted (Actual): September 25, 2018
• Last Update Submitted That Met QC Criteria: August 27, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Vomiting; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dermatologic Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Serotonin Antagonists; Anti-Anxiety Agents; Antipruritics; Neurokinin-1 Receptor Antagonists; Dexamethasone; Ondansetron; Aprepitant; Fosaprepitant
• Other Study ID Numbers: 0869-134; 2009_501 (Other Identifier: Telerx Study Identifier)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Study Data/Documents

1. CSR Snyopsis