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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Chemotherapy-Induced Nausea and Vomiting

Intervention / Treatment
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* Drug: Experimental: aprepitant
* Drug: Experimental: fosaprepitant
* Drug: Comparator: ondansetron
* Drug: Ondansetron
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part IA-fosaprepitant 115 mg/aprepitant<br>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<br>* aprepitant powder for suspension, 125 mg/sachet, PO<br>* Other names: MK-0869;Drug: Experimental: fosaprepitant<br>* fosaprepitant lyophilized powder for suspension, 115 mg/vial or 150 mg/vial, IV<br>* Other names: MK-0517;Drug: Ondansetron<br>* ondansetron solution for infusion, IV, administered per local standard of care<br>Drug: Dexamethasone<br>* dexamethasone solution for infusion, IV, administered per local standard of care<br>|
| Experimental: Part IB-fosaprepitant 150 mg<br>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<br>* fosaprepitant lyophilized powder for suspension, 115 mg/vial or 150 mg/vial, IV<br>* Other names: MK-0517;Drug: Ondansetron<br>* ondansetron solution for infusion, IV, administered per local standard of care<br>Drug: Dexamethasone<br>* dexamethasone solution for infusion, IV, administered per local standard of care<br>|
| Experimental: Part IIA-aprepitant 80 mg equiv.<br>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<br>* aprepitant powder for suspension, 125 mg/sachet, PO<br>* Other names: MK-0869;Drug: Ondansetron<br>* ondansetron solution for infusion, IV, administered per local standard of care<br>Drug: Dexamethasone<br>* dexamethasone solution for infusion, IV, administered per local standard of care<br>|
| Experimental: Part IIB-aprepitant 125 mg equiv.<br>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<br>* aprepitant powder for suspension, 125 mg/sachet, PO<br>* Other names: MK-0869;Drug: Ondansetron<br>* ondansetron solution for infusion, IV, administered per local standard of care<br>Drug: Dexamethasone<br>* dexamethasone solution for infusion, IV, administered per local standard of care<br>|
| Active Comparator: Part III-ondansetron<br>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: Comparator: ondansetron<br>* ondansetron solution for infusion, IV, administered per local standard of care<br>* Other names: Zofran;Drug: Dexamethasone<br>* dexamethasone solution for infusion, IV, administered per local standard of care<br>|
| Experimental: Part IV-aprepitant regimen<br>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<br>* aprepitant powder for suspension, 125 mg/sachet, PO<br>* Other names: MK-0869;Drug: Ondansetron<br>* ondansetron solution for infusion, IV, administered per local standard of care<br>Drug: Dexamethasone<br>* dexamethasone solution for infusion, IV, administered per local standard of care<br>|
| Experimental: Part V-fosaprepitant regimen<br>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<br>* fosaprepitant lyophilized powder for suspension, 115 mg/vial or 150 mg/vial, IV<br>* Other names: MK-0517;Drug: Ondansetron<br>* ondansetron solution for infusion, IV, administered per local standard of care<br>Drug: Dexamethasone<br>* dexamethasone solution for infusion, IV, administered per local standard of care<br>|

What is the study measuring?
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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 |