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

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: January 20, 2014

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.

Interventions

  • Drug: Experimental: aprepitant
    • aprepitant powder for suspension, 125 mg/sachet, PO
  • Drug: Experimental: fosaprepitant
    • fosaprepitant lyophilized powder for suspension, 115 mg/vial or 150 mg/vial, IV
  • Drug: Comparator: ondansetron
    • ondansetron solution for infusion, IV, administered per local standard of care
  • 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

Arms, Groups and Cohorts

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

Clinical Trial Outcome Measures

Primary Measures

  • Area Under the Time-Concentration Curve From 0 to 24 Hours (AUC 0-24hr) for Aprepitant
    • Time Frame: Up to 24 hours post fosaprepitant/aprepitant dose
    • 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.
  • Maximum Plasma Concentration (Cmax) for Aprepitant
    • Time Frame: Up to 72 hours post fosaprepitant/aprepitant dose
    • 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.
  • Time to Cmax (Tmax) for Aprepitant
    • Time Frame: Up to 72 hours post fosaprepitant/aprepitant dose
    • 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.
  • Apparent Terminal Half-life (t1/2) for Aprepitant
    • Time Frame: Up to 72 hours post fosaprepitant/aprepitant dose
    • 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.
  • Cmax for Fosaprepitant
    • Time Frame: Up to 72 hours post fosaprepitant dose
    • 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.
  • Tmax for Fosaprepitant
    • Time Frame: Up to 72 hours post fosaprepitant dose
    • 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.
  • Number of Participants Experiencing Adverse Events (AEs)
    • Time Frame: Up to 14 days after last dose of study drug (Up to 17 days)
    • 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.
  • Number of Participants Discontinuing Study Drug Due to an AE
    • Time Frame: Day 1 up to Day 3
    • 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.

Secondary Measures

  • Plasma Concentration and PK Parameters of Dexamethasone in Participants From Birth to 1 Year of Age
    • Time Frame: Up to 24 hours post dexamethasone dose
    • 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.

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: 17 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Merck Sharp & Dohme LLC
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Medical Director, Study Director, Merck Sharp & Dohme LLC

Citations Reporting on Results

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.

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