Efficacy and Safety Study of Fosaprepitant (MK-0517) Plus Ondansetron Versus Ondansetron Alone for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Participants (MK-0517-044)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of fosaprepitant (MK-0517) plus ondansetron versus ondansetron alone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in pediatric participants scheduled to receive chemotherapeutic agent(s) associated with moderate or high risk of causing emesis (vomiting), or chemotherapy agent(s) not previously tolerated due to vomiting. The primary hypothesis is that a single dose of fosaprepitant in combination with ondansetron provides superior control of CINV compared to ondansetron alone as measured by the percentage of participants with a Complete Response (no vomiting, no retching, and no use of rescue medications) in the delayed phase (>24 to 120 hours) following initiation of emetogneic chemotherapy in Cycle 1.

Detailed Description
-----------------
In Cycle 1, participants will receive double-blind study drug (fosaprepitant plus ondansetron with or without dexamethasone OR placebo to fosaprepitant plus ondansetron with or without dexamethasone). Upon completion of Cycle 1, participants may have the option to continue for up to 5 additional open-label cycles, receiving fosaprepitant plus ondansetron with or without dexamethasone.

Official Title
-----------------
A Phase III, Randomized, Placebo-Controlled Clinical Trial to Study the Efficacy and Safety of MK-0517/Fosaprepitant and Ondansetron Versus Ondansetron for the Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Pediatric Subjects Receiving Emetogenic Chemotherapy

Conditions
-----------------
Chemotherapy-induced Nausea and Vomiting

Intervention / Treatment
-----------------
* Drug: Fosaprepitant
* Drug: Placebo for fosaprepitant
* Drug: Ondansetron
* Drug: Dexamethasone
* Drug: 5-HT3 antagonist


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Is 0 (at least 37 weeks gestation) to 17 years of age at time of randomization Has a Lansky Play Performance score ≥60 (participants ≤16 years of age) or a Karnofsky score ≥60 (participants >16 years of age) Has a predicted life expectancy ≥3 months Is receiving chemotherapeutic agent(s) associated with moderate or high risk of emetogenicity, or a chemotherapy regimen not previously tolerated due to vomiting Has a preexisting functional central venous catheter available for study drug administration Is male OR is female who is not of reproductive potential OR is female who is of reproductive potential and agrees to avoid becoming pregnant in the 28 days prior to receiving study drug, while receiving study drug and for at least 30 days after last dose of study drug Exclusion Criteria: Has vomited in the 24 hours prior to chemotherapy initiation on Treatment Day 1 Has a symptomatic primary or metastatic central nervous system (CNS) malignancy with nausea and/or vomiting (asymptomatic participants may participate in study) Will be receiving stem cell rescue therapy in conjunction with study-related course of emetogenic chemotherapy or during the 14 days following administration of fosaprepitant/placebo for fosaprepitant Has received or will receive total body irradiation of radiation therapy to the abdomen or pelvis in the week prior to Treatment Day 1 and/or during the diary reporting period (120 hours following initiation of chemotherapy) Has had benzodiazepine, opioid or opioid like therapy initiated within 48 hours prior to study drug administration, or is expected to receive within 120 hours following initiation of chemotherapy except for single doses of midazolam, temazepam or triazolam Has started on systemic corticosteroid therapy within 72 hours prior to study drug administration or is expected to receive a corticosteroid as part of the chemotherapy regimen Is currently taking, or has taken within 48 hours of Treatment Day 1 the following drugs with antiemetic properties: 5-hydroxytryptamine 3 (5-HT3) antagonists (e.g., ondansetron), benzamides (e.g., haloperidol), cyclizine, domperidone, herbal therapies with potential antiemetic properties, olanzapine, phenothiazines (e.g., prochlorpenzine), scopolamine (this is not an exhaustive list) Is or has an immediate family member who is investigational site or sponsor staff directly involved with this study Is currently a user of any recreational or illicit drugs (including marijuana) or has current evidence of drug or alcohol abuse or dependence Is mentally incapacitated or has a significant emotional or psychiatric disorder Is pregnant or breast feeding Is allergic to fosaprepitant, aprepitant (MK-0869), ondansetron, or any other 5-HT3 antagonist Has a known history of QT prolongation or is taking any medication that is known to lead to QT prolongation Has an active infection (e.g., pneumonia), congestive heart failure, bradyarrhythmia, any uncontrolled disease (e.g., diabetic ketoacidosis, gastrointestinal obstruction) except for malignancy Has ever participated in a previous study of aprepitant or fosaprepitant or has taken an investigational drug with the last 4 weeks.

Ages Eligible for Study
-----------------
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fosaprepitant Regimen Cycle 1<br>Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) administered intravenously (IV) on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. | Drug: Fosaprepitant<br> <br> * Other names: EMEND for injection®;Drug: Ondansetron<br> <br> * Other names: Zofran®;Drug: Dexamethasone<br> <br> |
| Placebo Comparator: Control Regimen Cycle 1<br>Participants received a single dose of matched placebo for fosaprepitant IV on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. | Drug: Placebo for fosaprepitant<br> <br> Drug: Ondansetron<br> <br> * Other names: Zofran®;Drug: Dexamethasone<br> <br> |
| Experimental: Fosaprepitant Regimen Cycles 2-6<br>Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) IV on Day 1 prior to chemotherapy plus a 5-hydroxytryptamine 3 (5-HT3) antagonist on Day 1 prior to chemotherapy and per product label or standard of care. Participants may also have received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. | Drug: Fosaprepitant<br> <br> * Other names: EMEND for injection®;Drug: Dexamethasone<br> <br> Drug: 5-HT3 antagonist<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced a Complete Response During the Delayed Phase (>24 to 120 Hours Post Initiation of Chemotherapy) in Cycle 1 | Complete Response was defined as no vomiting, no retching, and no use of rescue medication following the initiation of emetogenic chemotherapy in Cycle 1. A vomiting episode was specified as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retching/dry heaves (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes were separated by the absence of emesis and retching for at least one minute. The date and time of each vomiting episode was recorded by participants in diaries at the time of occurrence. The percentage of participants with no vomiting and no retching episodes in the delayed phase, defined as the time period of >24 to120 hours post initiation of chemotherapy in Cycle 1, was calculated. | >24 to 120 hours post initiation of chemotherapy (1 to 15 days after the dose of study drug) | 
| Percentage of Participants Who Experienced One or More Adverse Events | An adverse event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug. A statistical analysis was performed for Tier 2 AEs in Cycle 1 to compare the percentage of participants who received fosaprepitant regimen and experienced at least 1 Tier 2 AE compared with the percentage of participants in the control regimen. The Tier 2 endpoint included broad clinical and laboratory AE categories consisting of the percentage of participants with any AE, drug-related AE, serious AE, and AEs that are both drug-related and serious. Tier 2 AEs were not pre-specified as events of interest and inclusion in the Tier 2 analysis required that at least 4 participants in any treatment group exhibited the AE. | Up to 6.5 months (up to 2 weeks after last dose of study drug) | 
| Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug. A statistical analysis was performed to compare the percentage of participants who discontinued in Cycle 1 due to an AE and received fosaprepitant regimen compared with the percentage of participants who received control regimen. | Up to 6 months (up to last dose of study drug) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced a Complete Response During the Acute Phase (0 to 24 Hours Post Initiation of Chemotherapy) in Cycle 1 | Complete Response was defined as no vomiting, no retching, and no use of rescue medication following the initiation of emetogenic chemotherapy in Cycle 1. A vomiting episode was specified as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retching/dry heaves (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes were separated by the absence of emesis and retching for at least one minute. The date and time of each vomiting episode was recorded by participants in diaries at the time of occurrence. The percentage of participants with no vomiting and no retching episodes in the acute phase, defined as the time period of 0 to 24 hours post initiation of chemotherapy in Cycle 1, was calculated. | 0 to 24 hours post initiation of chemotherapy (up to 1 day after the dose of study drug) | 
| Percentage of Participants Who Experienced a Complete Response During the Overall Phase (0 to 120 Hours Post Initiation of Chemotherapy) in Cycle 1 | Complete Response was defined as no vomiting, no retching, and no use of rescue medication following the initiation of emetogenic chemotherapy in Cycle 1. A vomiting episode was specified as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retching/dry heaves (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes were separated by the absence of emesis and retching for at least one minute. The date and time of each vomiting episode was recorded by participants in diaries at the time of occurrence. The percentage of participants with no vomiting and no retching episodes in the overall phase, defined as the time period of 0 to 120 hours post initiation of chemotherapy in Cycle 1, was calculated. | 0 to 120 hours post initiation of chemotherapy (up to 15 days after the dose of study drug) | 
| Percentage of Participants Who Experienced No Vomiting, Regardless of Rescue Medication Use, During the Overall Phase (0 to 120 Hours Post Initiation of Chemotherapy) in Cycle 1 | Vomiting was assessed, regardless of rescue medicine use, following the initiation of emetogenic chemotherapy in Cycle 1. A vomiting episode was specified as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retching/dry heaves (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes were separated by the absence of emesis and retching for at least one minute. The date and time of each vomiting episode was recorded by participants in diaries at the time of occurrence. Rescue medication was permitted to alleviate symptoms of established nausea or vomiting; but not as preventive medication. The percentage of participants with no vomiting and no retching episodes in the overall phase, defined as the time period of 0 to 120 hours post initiation of chemotherapy in Cycle 1, was calculated. | 0 to 120 hours post initiation of chemotherapy (up to 15 days after the dose of study drug) |