| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chemotherapy-induced nausea and vomiting (CINV) associated with emetogenic chemotherapy |
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| E.1.1.1 | Medical condition in easily understood language |
| Nausea and vomiting caused by chemotherapy |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036899 |
| E.1.2 | Term | Prophylaxis against chemotherapy induced vomiting |
| E.1.2 | System Organ Class | 100000004865 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Pharmacokinetics: To estimate aprepitant plasma concentration profiles and pharmacokinetic parameters by population analysis, including historical data (e.g., AUC0-∞, AUC0-24, Cmax, Tmax, t1/2, CL/F, C24hr, and C48hr), in pediatric patients from birth to 17 years old receiving emetogenic chemotherapy and administered a single dose of fosaprepitant concomitantly with IV ondansetron in Cycle 1 and compare to historical pharmacokinetic parameters obtained in adults.
Safety: To evaluate the safety and tolerability of the administered dose of fosaprepitant administered concomitantly with a 5-HT3 antagonist, in pediatric patients from birth to 17 years old receiving emetogenic chemotherapy in Cycles 1 to 6. |
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| E.2.2 | Secondary objectives of the trial |
| Pharmacokinetics: To estimate intravenous dexamethasone plasma concentration profiles and pharmacokinetic parameters (e.g. AUC0-∞, AUC0-24, Cmax, Tmax, t1/2, CL/F, C24hr, and C48hr) in patients birth to 1 year old receiving emetogenic chemotherapy, concomitant dexamethasone and IV ondansetron, and in the presence (Cycle 1) or absence (Cycle 2) of a single dose of fosaprepitant in the open-label portion of the study. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Future Biomedical Research:
Merck will conduct Future Biomedical Research on DNA (buccal swab) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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| E.3 | Principal inclusion criteria |
Inclusion Criteria in Cycle 1
1. Patient is 0 (at least 37 weeks gestation) to less than 12 years old at time of study entry (randomization). Prior to the current amendment patients up to 17 years old were randomized.
2. Parent/guardian (legally authorized representative) agrees to the patient’s participation as indicated by parent/legal guardian signature on the informed consent form. Patient 12 to 17 years old, or as required by local regulation, assents and has the ability to understand the nature and intent of the study including the ability to comply with study procedures, complete study diary, and is willing to keep scheduled study visits. The parent/guardian or patient may also provide consent/assent for Future Biomedical Research. However, the patient may participate in the main trial without participating in the Future Biomedical Research.
3. Patient is 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.
4. Patient is expected to receive ondansetron as part of their antiemetic regimen.
5. Female patient who has begun menses has a negative urine pregnancy test prior to Treatment Day 1 of each Study Cycle. A female patient who is of reproductive potential agrees to remain abstinent or use a barrier form of contraception for at least 28 days prior to, throughout, and for at least one month following the last dose of study medication. Women taking oral contraception must agree to add a barrier form of contraception. For countries where abstinence is not considered an acceptable method of birth control, a locally acceptable birth control method must be used.
6. Patient >16 years of age has a Karnofsky score ≥ 60; patient ≤ 16 years of age has a Lansky Play Performance score ≥ 60 (Appendix 6.3).
7. Patient has a predicted life expectancy of ≥ 3 months.
8. Patient has a preexisting functioning central venous catheter available for study drug administration.
9. Patient must weigh more than 3.0 kg. For patients weighing less than the 3rd percentile (based on local growth charts for age and gender) investigator judgment and consideration of overall health and growth should be used to determine participation.
Inclusion Criteria in Dexamethasone PK Sampling Cycle 2
The inclusion criteria in Cycle 1 will apply to patients birth to 1 year old entering Dexamethasone PK Sampling Cycle 2. Additional inclusion criteria for Dexamethasone PK Sampling Cycle 2 are as follows:
10. Parent/guardian (legally authorized representative), agrees to the patient's participation as indicated by parent/legal guardian signature on the informed consent form.
11. Patient participation in the study during a subsequent cycle of chemotherapy is considered appropriate by the investigator and will not pose unwarranted risk to the patient.
12. Patient has, in the opinion of the investigator, completed the preceding cycle of chemotherapy and related study procedures satisfactorily. If a patient experiences vomiting or uses rescue medication during a study cycle, they are permitted to participate in a subsequent study cycle provided they have complied with all required study procedures.
These patients will follow the inclusion criteria in section 2.2.3 for Cycle 3-6 if they choose to participate in additional Cycles.
Inclusion Criteria in Optional Cycles 2 to 6
The inclusion criteria in Cycle 1 will apply to patients entering Cycles 2 to 6, with the exception of Inclusion Criteria #1, 2, 4, 6, and 7. Inclusion criteria in Dexamethasone PK Sampling Cycle 2 (#10, 11 and 12 ) do not apply to patients entering Optional Cycles.
13. Parent/guardian (legally authorized representative) or patient, if patient is 18 years old, agrees to the patient's participation as indicated by parent/legal guardian (or patient, if patient is 18 years old) signature on the informed consent form. Patients 12 to 17 years old, or as required by local regulation, assents and has the ability to understand the nature and intent of the study including the ability to comply with study procedures and is willing to keep scheduled study visits.
14. Patient participation in the study during a subsequent cycle of chemotherapy is considered appropriate by the investigator and will not pose unwarranted risk to the patient.
15. Patient has, in the opinion of the investigator, completed the preceding cycle of chemotherapy and related study procedures satisfactorily. If a patient experiences vomiting or uses rescue medication during a study cycle, they are permitted to participate in a subsequent study cycle provided they have complied with all required study procedures.
16. Patient is expected to receive a 5-HT3 antagonist (e.g., ondansetron, granisetron) as part of their antiemetic regimen.
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| E.4 | Principal exclusion criteria |
Exclusion Criteria in Cycle 1
1. Patient has vomited in the 24 hours prior to chemotherapy initiation on Treatment Day 1.
2. Patient is currently a user of any illicit drugs (including marijuana) or has current evidence of alcohol abuse (defined using the Diagnostic and Statistical Manual-IV [DSM-IV] criteria) as determined by the investigator.
3. Patient is scheduled to receive stem cell rescue therapy in conjunction with study related course(s) of emetogenic chemotherapy or during the 14 days following administration of fosaprepitant.
4. Patient has received or will receive radiation therapy to the abdomen or pelvis in the week prior to Treatment Day 1 and/or during the diary reporting period (120 hours after initiation of chemotherapy).
5. Patient is pregnant or breast feeding. (Females of reproductive potential are required to have a negative urine pregnancy test prior to entering the study.)
6. Patient is allergic to fosaprepitant, aprepitant, ondansetron, or any other 5-HT3 antagonist.
7. Patient has a symptomatic primary or metastatic central nervous system (CNS) malignancy with nausea and/or vomiting. Patient who is asymptomatic is allowed to participate.
8. Patient has abnormal laboratory values as follows:
a. Bone Marrow Function
i. Peripheral absolute neutrophil count (ANC) <1000/mm3
ii. Platelet count <75,000/mm3
b. Liver Function
ii. Alanine aminotransferase (ALT) >5.0 x ULN for age
iii. Bilirubin >1.5 x ULN for age
c. Renal Function
i. Serum creatinine >1.5 x ULN for age
9. Patient has an active infection (e.g., pneumonia), congestive heart failure, bradyarrythmia, any uncontrolled disease (e.g., diabetic ketoacidosis, gastrointestinal obstruction) except for malignancy, or a history of any illness which in the opinion of the investigator, might confound the results of the study or pose unwarranted risk in administering study drug or concomitant therapy to the patient.
10. Patient is mentally incapacitated or has a significant emotional or psychiatric disorder that, in the opinion of the investigator, precludes study entry.
11. Patient has a known history of QT prolongation or is taking any medication that is known to lead to QT prolongation.
12. Patient has had benzodiazepine or opioid therapy initiated within 48 hours of study drug administration, except for single daily doses of triazolam, temazepam, or midazolam.
13. Patient has been started on systemic corticosteroid therapy within 72 hours prior to study drug administration or is planned to receive a corticosteroid as part of the chemotherapy regimen.
14. Patient is currently taking warfarin.
15. Patient has ever participated in a study of aprepitant or fosaprepitant, or has taken a non-approved (investigational) drug within the last 4 weeks prior to randomization.
16. Patient is taking or as taken other Excluded Medications as per protocol
Exclusion Criteria in Optional Cycles 2 to 6
The Exclusion Criteria in Cycle 1 will apply to patients entering Cycles 2 to 6, and Dexamethasone PK Sampling patients entering Cycles 3 to 6 with the exception of Exclusion Criterion #1, 3, 4 and 13.
The Exclusion Criteria in Cycle 1 will apply to patients entering Dexamethasone PK Sampling Cycle 2.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacokinetic (PK) Endpoints:Pharmacokinetic endpoints for aprepitant e.g. AUC0-∞, AUC0-24, Cmax, Tmax, t1/2, CL/F, C24hr, and C48hr will be estimated by population methods, including the use of historic data in the population modeling, in each age group for all fosaprepitant treatments in Cycle 1.
Safety Endpoints: Clinical and laboratory adverse events that are considered drug-related, serious, serious drug-related, or lead to discontinuation of study therapy.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PK samples for aprepitant to be collected at six time points: end of fosaprepitant infusion; 2-4 h, 5 -7 h, 8 - 10 h, 23 -25 h, 46 -50 h after completion of fosaprepitant infusion.
For Safety: Throughout the study (Screening, Treatment, Post- Treatment, and/or Follow-Up/DC).
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| E.5.2 | Secondary end point(s) |
Pharmacokinetic (PK) Endpoints: Pharmacokinetic endpoints of dexamethasone including AUC0-∞, AUC0-24, Cmax, Tmax, t1/2, CL/F, and C24hr, will also be estimated if available.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Plasma for PK dexamethasone analysis will be obtained in Cycle 1 at the time points described above and immediately following dexamethasone administration. Plasma for PK analysis will be obtained in Cycle 2 at the following time points: prior to dexamethasone administration, immediately following dexamethasone administration, 2 -4 h after start of dexamethasone administration, 5 - 7 h after dexamethasone administration, 8 - 10 h after dexamethasone administration, and 23 – 25 h after dexamethasone administration
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Argentina |
| Brazil |
| Canada |
| Chile |
| Korea, Republic of |
| Peru |
| Russian Federation |
| South Africa |
| Turkey |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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