Status:Not yet recruiting
Keywords:Fosaprepitant , CINV , Chemotherapy , Ondansetron
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 of age by assessing pharmacokinetic (PK) and pharmacodynamic (PD) parameters, and monitoring safety and tolerability of the administered doses in order to prevent nausea and vomiting in pediatric patients treated with highly or moderately emetogenic chemotherapy.
Objective: To estimate aprepitant plasma concentration profiles and pharmacokinetic parameters by population analysis, including historical data (e.g., Cmax, Tmax, AUC0-∞, t1/2, CL/F), for Doses 1, 2, and 3, in pediatric patients from birth to 17 years of age receiving emetogenic chemotherapy and administered a single dose of fosaprepitant concomitantly with IV ondansetron in Cycle 1.
Objective: To evaluate the safety and tolerability of the administered dose of fosaprepitant, concomitantly with IV ondansetron, in pediatric patients from birth to 17 years of age receiving emetogenic chemotherapy in Cycle 1.
Objective 1: To explore the efficacy of fosaprepitant Doses 1, 2, and 3, administered concomitantly with IV ondansetron, in the control of CINV in patients birth to 17 years of age with respect to Complete Response (no vomiting, no retching, and no use of rescue medication) in the 25 to 120 hours following the initiation of emetogenic chemotherapy in Cycle 1 (Delayed Phase).
Objective 2: To explore the efficacy of fosaprepitant Doses 1, 2, and 3, administered concomitantly with IV ondansetron, in the control of CINV in patients birth to 17 years of age with respect to Complete Response (no vomiting, no retching, and no use of rescue medication) in the 0 to 120 hours following the initiation of emetogenic chemotherapy in Cycle 1 (Overall Phase).
Objective 3: To explore the efficacy of fosaprepitant Doses 1), 2, and 3, administered concomitantly with IV ondansetron, in the control of CINV in patients birth to 17 years of age with respect to Complete Response (no vomiting, no retching, and no use of rescue medication) in the 0 to 24 hours following the initiation of emetogenic chemotherapy in Cycle 1 (Acute Phase).
Objective 4: To explore the efficacy of fosaprepitant Doses 1, 2, and 3, administered concomitantly with IV ondansetron, in the control of CINV in patients birth to 17 years of age with respect to No Vomiting in the 0 to 120 hours, 0 to 24 hours, and 25 to 120 hours following the initiation of emetogenic chemotherapy in Cycle 1.
Objective 5: To compare the pharmacokinetic parameters (AUC and Cmax) estimated with population methods in pediatric patients following administration of IV fosaprepitant in Cycle 1 to the pharmacokinetic parameters obtained in adults.
Objective: To describe the adverse event profile of the fosaprepitant regimen when administered to pediatric cancer patients receiving additional cycles of emetogenic chemotherapy.
1. Patient is 0 (at least 37 weeks gestation) to 17 years of age at time of study entry (randomization).
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 of age, 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 randomization. A female patient who is of reproductive potential agrees to remain abstinent or use a barrier form of contraception for at least 14 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 >10 years of age has a Karnofsky score ≥60; patient ≤10 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’s weight should not be less than the 3rd percentile for age and gender (and no less than 3.0 kg) per investigator judgment using available local growth chart(s).
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, and 4.
Additional inclusion criteria for Cycles 2 to 6 are as follows:
a. 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 of age, 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.
b. 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.
c. 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.
d. Patient is expected to receive a 5-HT3 antagonist (e.g., ondansetron, granisetron) as part of their antiemetic regimen.
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.
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 course of the study.
5. Patient is pregnant or breast feeding. (Females of child bearing potential are required to have a negative urine pregnancy test prior to ntering 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 causing nausea and/or vomiting. Patient who is asymptomatic is allowed to participate.
8. Patient has abnormal laboratory values as follows (deviations from these guidelines require discussion with the Merck Clinical Monitor):
a.BoneMarrowFunction i. Peripheral absolute neutrophil count (ANC) <1000/mm3 ii. Platelet count <100,000/mm3
b. Liver Function i. Aspartate aminotransferase (AST) >5.0 x upper limit of normal (ULN) for age 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.
- 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 hours prior to study drug administration or is planned to receive a corticosteroid as part of the chemotherapy regimen.
Patients who are receiving chronic (>72 hours), 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. 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: NOTE: The list of cytochrome P450 isoenzyme 3A4 (CYP3A4) and antiemetic medications in Table 2-1 is not exhaustive. The SPONSOR should be consulted in individual cases where the patient is taking a strong CYP3A4 inducer/inhibitor (not including chemotherapy agents) or antiemetic not listed in Table 2-1.
Excluded Medications - Table 2.1
Patient is taking, or has taken within 30 days of Treatment Day 1
16. CYP3A4 Inducers
Phenytoin or carbamazepine, Barbiturates, Rifampicin or rifabutin, St. John’s Wort
Patient is taking, or has taken within 7 days of Treatment Day 1
17. CYP3A4 Substrates
Terfenadine, Cisapride, Astemizole, Pimozide, Amifostine, Marinol
Clarithromycin, Erythromycin, Telithromycin, Ketoconazole, Itraconazole, Fluconazole, Nefazodone, Troleandomycin, Ritonavir, Nelfinavir Posaconazole
Patient has taken an antiemetic within 48 hours of Treatment Day 1.
5HT3 antagonists (e.g., ondansetron), Phenothiazines (e.g., prochlorperazine), Butyrophenones (e.g., haloperidol), Benzamides (e.g., metoclopramide), Domperidone, Herbal therapies with potential antiemetic properties, Scopolamine, Cyclizine
A Azithromycin is a macrolide antibiotic that is permitted during the study period
CYP3A4 = cytochrome P450 isoenzyme 3A4
Cycles 2 to 6
The exclusion criteria in Cycle 1 will apply to patients entering Cycles 2 to 6, with the exception of Exclusion Criterion #1.