| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Efficacy: To compare the single IV dose of fosaprepitant (in combination with ondansetron) to the ondansetron alone regimen with respect to the efficacy endpoint of Complete Response in the delayed phase (>24 to 120 hours) following the initiation of emetogenic chemotherapy in Cycle 1. Safety: To assess the safety and tolerability of the fosaprepitant regimen in pediatric subjects who are receiving emetogenic chemotherapy. |
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| E.2.2 | Secondary objectives of the trial |
To compare the fosaprepitant regimen to the control regimen with respect to the efficacy endpoint of Complete Response in the acute (0 to 24 hours) and overall phases (0 to 120 hours) following the initiation of emetogenic chemotherapy in Cycle 1.
To compare the fosaprepitant regimen to the control regimen with respect to the efficacy endpoint of No Vomiting, regardless of rescue medication use, in the overall phase (0 to 120 hours) following the initiation of emetogenic chemotherapy in Cycle 1.
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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 |
| Merck will conduct Future Biomedical Research on DNA (buccal) 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 |
In order to be eligible for participation in this trial, the subject must, for cycle 1:
1.have parent/legal guardian (legally authorized representative) agreement to the subject’s participation as indicated by parent/legal guardian signature on the informed consent form. Subject 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/legal guardian or subject may also provide consent/assent for Future Biomedical Research (FBR). However, the subject may participate in the main trial without participating in the FBR.
2.be 0 (at least 37 weeks gestation) to 17 years of age at time of randomization.
3.have a Lansky Play Performance score ≥60 (subjects ≤16 years of age) or a Karnofsky score ≥60 (subjects >16 years of age) as defined in Section 12.4 –Lansky and Karnofsky Performance Status Scales.
4.have a predicted life expectancy ≥3 months.
5.be receiving chemotherapeutic agent(s) associated with moderate or high risk of emetogenicity for a documented malignancy, or a chemotherapy regimen not previously tolerated due to vomiting. See Section 12.5 – Emetogenicity of Commonly Used Chemotherapeutic Agents and Radiation Therapy, for guidance on the classification of chemotherapeutic agents.
Cycle 1 only: If a subject’s chemotherapy regimen has multiple chemotherapies with different emetogenic potential, then the most emetogenic agent must be part of the Day 1 regimen.
6.have a preexisting functional central venous catheter available for study drug administration.
7.Meet one of the following:
If the subject is a female who is of reproductive potential, the subject must: have a negative urine pregnancy test prior to fosaprepitant dosing in a cycle; must agree to avoid becoming pregnant in the 28 days prior to receiving study drug, while receiving study drug and for at least 30 days (or local standard of care if longer) after the last dose of study drug (including the optional cycles) by complying with one of the following: (1) practice abstinence from heterosexual activity OR (2) use (or have her partner use) acceptable contraception during heterosexual activity.
The subject is a male.
The subject is a female who is not of reproductive potential, defined as a female who either: (1) has not begun menses; (2) has had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; OR (3) has a congenital or acquired condition that prevents childbearing.
In order to be eligible for participation in an optional cycle, subject must meet inclusion criteria 5, 6 and 7 above in addition to the following:
8.have completed the preceding study cycle and related study procedures satisfactorily, have no unresolved drug related adverse events and continued participation in an optional cycle poses no unwarranted risk to the subject as determined by the investigator.
9.have parent/legal guardian (legally authorized representative) or subject (if subject is 18 years old) agreement to the subject’s participation as indicated by parent/legal guardian or subject (if subject is 18 years old) signature on the informed consent form for the optional cycles. Subject 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.
Refer to Protocol for complete list
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| E.4 | Principal exclusion criteria |
The subject must be excluded from participating in the trial if:
Exclusion criteria for Cycle 1 only:
1.has vomited in the 24 hours prior to chemotherapy initiation on Treatment Day 1.
2.has a symptomatic primary or metastatic central nervous system (CNS) malignancy with nausea and/or vomiting. Subject who is asymptomatic is allowed to participate.
3.has abnormal laboratory values as follows:
•peripheral absolute neutrophil count (ANC) <1000/mm3
•platelet count <75,000/mm3
•aspartate aminotransferase (AST) >5.0 x upper limit of normal (ULN) for age
•alanine aminotransferase (ALT) >5.0 x ULN for age
•bilirubin >1.5 x ULN for age
•creatinine >1.5 x ULN for age
4.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.
5.has received or will receive total body irradiation or radiation therapy to the abdomen (includes the level of the diaphragm and below) or pelvis in the week prior to Treatment Day 1 and/or during the diary reporting period (120 hours following initiation of chemotherapy).
6.has had benzodiazepine (potential to alleviate nausea and vomiting), opioid or opioid like (e.g., tramadol hydrochloride) therapy (potential to enhance nausea and vomiting) initiated within 48 hours prior to study drug administration, or is expected to receive within 120 hours following initiation of chemotherapy, except for single daily doses of midazolam, temazepam or triazolam. Continuation of chronic benzodiazepine, opioid or opioid like therapy is permitted provided it was initiated at least 48 hours prior to study drug administration.
7.has been 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.
Exceptions:
subject who is 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, subject is 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.
8.is currently taking, or has taken within 48 hours of Treatment Day 1 the following drugs with antiemetic properties: 5-HT3 antagonists (e.g., ondansetron), benzamides (e.g., metoclopramide), butyrophenones (e.g., haloperidol), cyclizine, domperidone, herbal therapies with potential antiemetic properties, olanzapine, phenothiazines (e.g., prochlorpenzine), scopolamine. Note: This is not an exhaustive list. The Sponsor should be consulted in individual cases where the subject is taking an antiemetic not listed above.
Exclusion criteria for Cycle 1 and optional Cycles 2 to 6:
9.is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial.
10.is currently a user of any recreational or illicit drugs (including marijuana) or has current evidence of drug or alcohol abuse or dependence as determined by the investigator.
11.is mentally incapacitated or has a significant emotional or psychiatric disorder that, in the opinion of the investigator, precludes study entry.
12.is pregnant or breast feeding.
13.is allergic to fosaprepitant, aprepitant, ondansetron, or any other 5-HT3 antagonist.
14.has a known history of QT prolongation or is taking any medication that is known to lead to QT prolongation.
15.has an active infection (e.g., pneumonia), congestive heart failure, bradyarrythmia, any uncontrolled disease (e.g., diabetic ketoacidosis, gastrointestinal obstruction) except for malignancy, or has 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 subject.
16.has ever participated in a previous study of aprepitant or fosaprepitant or has taken a non-approved (investigational) drug within the last 4 weeks. Note: Subjects in investigational studies with marketed chemotherapeutic agents (whether explicitly for children or only marketed for adults and usually administered in children with the appropriate dose adjustments) are allowed to enroll if they fulfill all other entry criteria. Previous or current participation in an observational study is acceptable.
17.is currently taking, or has taken a CYP3A4 inducer (within 30 days of Treatment Day 1), a CYP3A4 substrate or inhibitor (within 7 days of Treatment Day 1) or is expected to receive within 120 hours following initiation of chemotherapy. Or, is currently taking warfarin or is expected to receive within 2 weeks following initiation of chemotherapy
Refer to Protocol for complete list
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy endpoint: the proportion of subjects with Complete Response in the >24 to 120 hours following initiation of emetogenic chemotherapy.
Safety endpoints: clinical and laboratory adverse events that are considered drug-related, serious, serious drug-related, or that lead to discontinuation from the study
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy: 0-120 hours following initiation of emetogenic chemotherapy in Cycle 1
Safety: Throughout the study
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| E.5.2 | Secondary end point(s) |
•comparing the fosaprepitant regimen to the control regimen with respect to the proportion of subjects reporting Complete Response in the acute phase (0 to 24 hours);
•comparing the fosaprepitant regimen to the control regimen with respect to the proportion of subjects reporting Complete Response in the overall phase (0 to 120 hours)
•comparing the fosaprepitant regimen to the control regimen with respect to the proportion of subjects with no vomiting in the overall phase (0 to 120 hours).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Cycle 1: the 0-24 hours following initiation of emetogenic chemotherapy and the 0 to 120 hours following initiation of emetogenic chemotherapy |
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Brazil |
| Chile |
| Colombia |
| Estonia |
| Finland |
| Germany |
| Greece |
| Hungary |
| Korea, Democratic People's Republic of |
| Lithuania |
| Mexico |
| Netherlands |
| Norway |
| Peru |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Sweden |
| 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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| LSLV - Last Subject Last visit |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 7 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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