Clinical trial NCT01697579: Study of the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Fosaprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Children (MK-0517-029)
Official title: A Phase IIb, Partially-Blinded, Randomized, Active Comparator-Controlled Study to Evaluate the Pharmacokinetics/Pharmacodynamics, Safety, and Tolerability of Fosaprepitant in Pediatric Patients for the Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) Associated With Emetogenic Chemotherapy Sub-title: Open-Label Cohort to Further Evaluate the Pharmacokinetics/Pharmacodynamics, Safety, and Tolerability of Fosaprepitant in Pediatric Patients Birth to <12 Years Old
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chemotherapy-induced Nausea and Vomiting
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2012-10-02
Enrollment: 240
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to determine the appropriate dosing regimen of fosaprepitant, when administered with ondansetron (with or without dexamethasone), for the prevention of CINV in children from birth to \<17 years of age. Fosaprepitant is a prodrug to aprepitant. All participants who completed the randomized Cycle 1 could elect to receive open-label fosaprepitant during optional Cycles 2-6.

Detailed description: Under Amendment 01, 0517-029 enrolled participants in the following age cohorts: 2-\<6, 6-\<12 and 12-17 years old. The study was randomized, partially-blinded, with parallel group assignment. Participants were randomized to one of three fosaprepitant doses or the control group. (Amendment 02 and Amendment 03 were country-specific amendments in Brazil that were required as per local regulations with no change in study design.) Under Amendment 04, the 12-17 year-old cohort was closed since that cohort fully enrolled. An additional fosaprepitant dose was added and all participants were allocated to this one treatment group. Amendment 04 was open-label and enrolled participants in the following age cohorts: 0-\<2, 2-\<6 and 6-\<12 years old.

Eligibility criteria: Inclusion Criteria:

* Is 0 months (at least 37 weeks gestation) to \<18 years of age
* Scheduled to receive chemotherapeutic agent(s) associated with moderate, high, or very high risk of emetogenicity for no more than 5 consecutive days for a documented malignancy, or a chemotherapy regimen not previously tolerated due to vomiting
* Expected to receive ondansetron as part of antiemetic regimen (Cycle 1); Expected to receive a 5-HT3 antagonist as part of antiemetic regimen (Cycles 2-6)
* If female and has begun menstruating, must have a negative pregnancy test prior to study participation and agree to remain abstinent or use a barrier form of contraception
* Predicted life expectancy of ≥3 months
* Pre-existing functioning central venous catheter
* Weight ≥3rd percentile for age and gender (and ≥3.0 kg)

Exclusion Criteria:

* Vomited in the 24 hours prior study drug administration (Cycle 1)
* Current user of any illicit drugs (including marijuana) or current evidence of alcohol abuse
* Scheduled to receive stem cell rescue therapy in conjunction with study related course(s) of emetogenic chemotherapy
* Received or will receive radiation therapy to the abdomen or pelvis in the week prior to study drug administration and/or during the course of the study
* Pregnant or breast feeding
* Allergic to fosaprepitant, aprepitant, ondansetron, or any other 5-HT3 antagonist
* Has a symptomatic central nervous system (CNS) tumor causing nausea and/or vomiting
* Has an active infection, congestive heart failure, slow heart rate, or other uncontrolled disease other than cancer
* Mentally incapacitated or has a significant emotional or psychiatric disorder
* Known history of QT prolongation or is taking any medication known to lead to QT prolongation
* Taking other excluded medications
* Participated in any previous study of aprepitant or fosaprepitant, or taken an investigational drug within 4 weeks prior to study participation

Primary outcomes:
measure: Maximum Concentration (Cmax) of Aprepitant in Participants 0 to <2 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Time to Maximum Concentration (Tmax) of Aprepitant in Participants 0 to <2 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Area Under the Concentration-time Curve of Aprepitant From Time 0 to Infinity (AUC 0-∞) in Participants 0 to <2 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Area Under the Concentration-time Curve of Aprepitant From Time 0 to 24 Hours (AUC 0-24hr) in Participants 0 to <2 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Apparent Terminal Half-life (t1/2) of Aprepitant in Participants 0 to <2 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Concentration of Aprepitant After 24 Hours (C24hr) in Participants 0 to <2 Years of Age
timeFrame: Approximately 24 hours (from 23 to 25 hours) post-infusion
measure: Concentration of Aprepitant After 48 Hours (C48hr) in Participants 0 to <2 Years of Age
timeFrame: Approximately 48 hours (from 46 to 50 hours) post-infusion
measure: Apparent Total Body Clearance (CL/F) of Aprepitant in Participants 0 to <2 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Cmax of Aprepitant in Participants 2 to <6 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Tmax of Aprepitant in Participants 2 to <6 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: AUC 0-∞ of Aprepitant in Participants 2 to <6 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: AUC 0-24hr of Aprepitant in Participants 2 to <6 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: t1/2 of Aprepitant in Participants 2 to <6 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: C24hr of Aprepitant in Participants 2 to <6 Years of Age
timeFrame: Approximately 24 hours (from 23 to 25 hours) post-infusion
measure: C48hr of Aprepitant in Participants 2 to <6 Years of Age
timeFrame: Approximately 48 hours (from 46 to 50 hours) post-infusion
measure: CL/F of Aprepitant in Participants 2 to <6 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Cmax of Aprepitant in Participants 6 to <12 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Tmax of Aprepitant in Participants 6 to <12 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: AUC 0-∞ of Aprepitant in Participants 6 to <12 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: AUC 0-24hr of Aprepitant in Participants 6 to <12 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: t1/2 of Aprepitant in Participants 6 to <12 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: C24hr of Aprepitant in Participants 6 to <12 Years of Age
timeFrame: Approximately 24 hours (from 23 to 25 hours) post-infusion
measure: C48hr of Aprepitant in Participants 6 to <12 Years of Age
timeFrame: Approximately 48 hours (from 46 to 50 hours) post-infusion
measure: CL/F of Aprepitant in Participants 6 to <12 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Cmax of Aprepitant in Participants 12 to 17 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Tmax of Aprepitant in Participants 12 to 17 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: AUC 0-∞ of Aprepitant in Participants 12 to 17 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: AUC 0-24hr of Aprepitant in Participants 12 to 17 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: t1/2 of Aprepitant in Participants 12 to 17 Years of Age Hours
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: C24hr of Aprepitant in Participants 12 to 17 Years of Age
timeFrame: Approximately 24 hours (from 23 to 25 hours) post-infusion
measure: C48hr of Aprepitant in Participants 12 to 17 Years of Age
timeFrame: Approximately 48 hours (from 46 to 50 hours) post-infusion
measure: CL/F of Aprepitant in Participants 12 to 17 Years of Age
timeFrame: Pre-infusion, immediately after infusion, and 2-4, 5-7, 8-10, 23-25, and 46-50 hours post-infusion
measure: Percentage of Participants Who Experienced at Least One Adverse Event (AE) in Cycle 1
timeFrame: Up to 14 days postdose in Cycle 1
measure: Percentage of Participants Who Experienced at Least One Adverse Event (AE) in Cycles 2-6
timeFrame: Up to 14 days postdose for each cycle (Cycles 2-6)
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Mora J, Valero M, DiCristina C, Jin M, Chain A, Bickham K. Pharmacokinetics/pharmacodynamics, safety, and tolerability of fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in pediatric cancer patients. Pediatr Blood Cancer. 2019 Jun;66(6):e27690. doi: 10.1002/pbc.27690. Epub 2019 Mar 21.