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 | 19.0 |
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 |
The purpose of this study is to determine the appropriate dosing regimen of fosaprepitant for the prevention of CINV in pediatric patients birth to 17 years old by assessing pharmacokinetic (PK) and pharmacodynamic (PD) parameters, and monitoring safety and tolerability of the administered doses.
Additionally, the pharmacokinetics of intravenous dexamethasone in patients birth to 1 year old treated with ondansetron and/or fosaprepitant will be evaluated to validate the need for reduction of the dose of dexamethasone in this age group. |
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E.2.2 | Secondary objectives of the trial |
The efficacy of fosaprepitant when administered concomitantly with ondansetron, with or without dexamethasone, will be explored in these pediatric patients receiving emetogenic chemotherapy (very high emetogenic chemotherapy [VHEC], HEC, or MEC), or a chemotherapy regimen not previously tolerated due to vomiting, for a documented malignancy.
The efficacy of fosaprepitant will also be explored after a delayed dose, approximately 24 hours after initiation of emetogenic chemotherapy, in these patients. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For Cyc 1: Criteria specific to patients 12-17 yrs old are only applicable to the partially-blinded portion of the study. The open-label portion of the study will not recruit patients 12-17yrs.
1. Patient is 0 (at least 37 weeks gestation) to less than 12 yrs at time of study entry (randomization).
2. Parent/guardian (legally auth. repr.) agrees to the patient’s participation as indicated by parent/legal guardian signature on the informed consent form (ICF). Patient 12-17 yrs 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 (FBR). However, the patient may participate in the main trial without participating in the FBR.
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 yrs has a Karnofsky score ≥ 60; patient ≤ 16 yrs has a Lansky Play Performance score ≥ 60.
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.
For Dexamethasone PK Sampling Cyc 2: The inclusion criteria in Cyc 1 will apply to patients birth to 1 yr old entering Dexamethasone PK Sampling Cyc 2. Add. incl. criterias for the group:
- Parent/guardian (legally auth. repr.), agrees to the patient's participation as indicated by parent/legal guardian signature on the ICF.
- 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.
- 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.
For Optional Cyc 2-6: The inclusion criteria in Cyc 1 will apply to patients entering Cyc 2-6, with exceptions of Incl. Criteria #1, 2, 4, 6, 7 and all of the Incl. criterias in Dexamethasone PK Sampling Cyc 2 do not apply to patients entering Optional Cycles. Add. incl. criterias:
- Parent/guardian (legally auth. repr.) or patient, if patient is 18 yrs, agrees to the patient's participation as indicated by parent/legal guardian (or patient, if patient is 18 yrs) signature on the ICF. Patients 12-17 yrs, 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.
- 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.
- 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.
- Patient is expected to receive a 5-HT3 antagonist as part of their antiemetic regimen.
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E.4 | Principal exclusion criteria |
For Cycle 1:
1. Patient has vomited in the 24 hrs prior to chemotherapy initiation on Treatment Day 1.
2. Patient is currently a user of any illicit drugs 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 hrs after chemotherapy initiation).
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 (peripheral absolute neutrophil count <1000/mm3; Platelet count <75,000/mm3)
b. Liver Function (Aspartate aminotransferase >5.0 x upper limit of normal f(ULN) or age; Alanine aminotransferase >5.0 x ULN for age; Bilirubin >1.5 x ULN for age)
c. Renal Function (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 hrs of study drug administration, except for single daily doses of triazolam, temazepam, or midazolam.
• Continuation of chronic benzodiazepine or opioid therapy is permitted provided it was initiated at least 48 hours prior to study drug administration.
13. Patient has been started on systemic corticosteroid therapy within 72 hrs prior to study drug administration or is planned to receive a corticosteroid as part of the chemotherapy regimen.
Exceptions:
• Patients who are receiving chronic (>72 hrs), daily steroid therapy can be enrolled provided the steroid dose is not >0.14 mg/kg (up to 10 mg) of prednisone daily or equivalent.
• For supportive care, patients are permitted to receive a single dose of corticosteroid within 3 days prior (but not on the day of study drug administration) provided it is less than the equivalent of 20 mg of prednisone.
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. Note: Patients in investigational studies with marketed chemotherapeutic agents (whether explicitly for children or only marketed for adults and usually administered to children with the appropriate dose adjustments) are allowed to enroll if they fulfill all other entry criteria.
16.-19.Other Excluded Medications: NB! The list of cytochrome P450 isoenzyme 3A4 (CYP3A4) and antiemetic medications in Table 2-1 is not exhaustive: sponsor should be consulted in individual cases where the patient is taking a strong CYP3A4 inducer/inhibitor or antiemetic not listed in Table 2-1.
Exclusion Criteria in Optional Cyc 2-6:
The Exclusion Criteria in Cyc 1 will apply to patients entering Cyc 2-6, and Dexamethasone PK Sampling patients entering Cyc 3-6 with the exception of Exclusion Criterion #1, 3, 4, 13.
The Exclusion Criteria in Cyc 1 will apply to patients entering Dexamethasone PK Sampling Cyc 2.
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E.5 End points |
E.5.1 | Primary end point(s) |
- Pharmacokinetic (PK) Endpoints
for aprepitant: AUC0-infinity, 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.
for dexamethasone: AUC0-infinity, AUC0-24, Cmax, Tmax, t1/2, CL/F, and C24hr, will also be estimated if available.
- 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 |
6 Time Points for PK Sampling Following-
Single Dose of Fosaprepitant:
1) End of the fosaprepitant infusion;
2) 2-4 hrs after (completion of) fosaprepitant inf.;
3) 5-7 hrs after fosaprepitant inf.;
4) 8-10 hrs after fosaprepitant inf.;
5) 23-25 hrs after fosaprepitant inf.;
6) 46-50 hrs after fosaprepitant inf. (patients who are unable to have this sample drawn will not be excluded);
or Single Dose of Dexamethasone:
1) Prior to dexamethasone admin.;
2) Immediately following dexamethasone admin.;
3) 2-4 hrs after (start of) dexamethasone admin.;
4) 5-7 hrs after dexamethasone admin.;
5) 8-10 hrs after dexamethasone admin.;
6) 23-25 hrs after dexamethasone admin..
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) |
- Pharmacodynamic assessments will be performed for Cycle 1 and possibly in patients birth to 1 year old participating in Dexamethasone PK Sampling in Cycle 2. The pharmacodynamic efficacy endpoint of most interest will be the proportion of patients with Complete Response (no vomiting, no retching, and no use of rescue medication) in the 25 to 120 hours post initiation of chemotherapy (delayed phase). Other pharmacodynamic efficacy endpoints will be: (1) the proportion of patients with Complete Response in the 0 to 24 hours post initiation of chemotherapy (acute phase); (2) the proportion of patients with Complete Response in the 0 to 120 hours post initiation of chemotherapy (overall phase); and (3) the proportion of patients with No Vomiting, irrespective of use of rescue medication, in the overall, acute, and delayed phases. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For PD: PD assessments will begin at the initiation of chemotherapy infusion (0 hours; Tzero) until Day 6 (~120 hours) after chemotherapy in Cycle 1 only. |
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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 | No |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Austria |
Brazil |
Canada |
Chile |
Colombia |
Estonia |
Germany |
Greece |
Hungary |
India |
Italy |
Korea, Republic of |
Lithuania |
Mexico |
Peru |
Portugal |
Romania |
Russian Federation |
South Africa |
Spain |
Turkey |
Ukraine |
United Kingdom |
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.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |