A Study of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the pharmacokinetics (PK), safety and tolerability of multiple doses of intravenous (IV) and oral isavuconazonium sulfate administered daily in pediatric patients. The PK data will be utilized to establish a pediatric population PK model of isavuconazole, the active moiety of isavuconazonium sulfate.

Official Title
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A Phase 1, Open-label, Multicenter, Non-comparative Pharmacokinetics and Safety Study of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients

Conditions
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Hematological Malignancy

Intervention / Treatment
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* Drug: isavuconazonium sulfate - intravenous
* Drug: isavuconazonium sulfate - oral


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has sufficient venous access to permit administration of study drug (for the IV cohorts), collection of pharmacokinetic samples and monitoring of safety laboratories. Female subject must either: Be of non-childbearing potential: Clearly premenarchal or documented surgically sterile Or, if of childbearing potential: Agree not to try to become pregnant during the study and for 28 days after the final study drug administration; and have a negative urine or serum pregnancy test at screening; and, if heterosexually active, agree to consistently use 2 forms of highly effective birth control (at least one of which must be a barrier method) starting at screening and throughout the study and for 28 days after the final study drug administration. Female subject who is of childbearing potential must agree not to breastfeed starting at screening and throughout the study and for 28 days after the final study drug administration. Female subject who is of childbearing potential must not donate ova starting at screening and throughout the study and for 28 days after the final study drug administration. Male subject who is of childbearing potential and their female spouse/partner who is of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (at least one of which must be a barrier method) starting at screening and continue throughout the study, and for 90 days after the final study drug administration. Male subject who is of childbearing potential must not donate sperm starting at screening and throughout the study and, for 90 days after the final study drug administration. Subject and subject's parent(s) or legal guardian agree that the subject will not participate in another interventional study while on treatment. For oral cohorts: subject is able to swallow the oral capsule medication. Exclusion Criteria: Subject has familial short QT syndrome, is receiving medications that are known to shorten the QT interval, or has a clinically significant abnormal electrocardiogram (ECG). Subject has evidence of hepatic dysfunction defined as: Total bilirubin ≥ 3 times the upper limit of normal (ULN) Alanine transaminase or aspartate transaminase ≥ 5 times the ULN Known cirrhosis or chronic hepatic failure Subject has used strong cytochrome P450 (CYP) 3A4 inhibitors or inducers such as ketoconazole, rifampin/rifampicin, long acting barbiturates, carbamazepine and St. John's wort in the 5 days prior to the first administration of study drug. Subject has known history of allergy, hypersensitivity, or any serious reaction to any of the azole class antifungals. Subject has any condition which makes the subject unsuitable for study participation. Subject is unlikely to survive 30 days. Subject has received investigational therapy, with the exception of oncology drug trials, within 28 days or 5 half-lives, whichever is longer, prior to screening. For oral cohorts: The subject has gastrointestinal disease or has had a procedure that is expected to interfere with the oral absorption or tolerance of the study drug (e.g., functionally relevant gastrointestinal obstruction, mucositis/stomatitis, or frequent vomiting). Subject previously dosed with isavuconazonium sulfate.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: isavuconazonium sulfate IV cohort 1: 1 to < 6 years of age<br>Patients will receive an intravenous (IV) loading regimen of isavuconazonium sulfate, which consists of a dose every 8 hours (+/- 2 hours) on days 1 and 2, followed by once daily IV maintenance dosing for up to 26 additional days (for a maximum of 28 days of dosing). | Drug: isavuconazonium sulfate - intravenous<br>* IV infusion<br>* Other names: Cresemba®;|
| Experimental: isavuconazonium sulfate IV cohort 2: 6 to < 12 years of age<br>Patients will receive an IV loading regimen of isavuconazonium sulfate, which consists of a dose every 8 hours (+/- 2 hours) on days 1 and 2, followed by once daily IV maintenance dosing for up to 26 additional days (for a maximum of 28 days of dosing). | Drug: isavuconazonium sulfate - intravenous<br>* IV infusion<br>* Other names: Cresemba®;|
| Experimental: isavuconazonium sulfate IV cohort 3: 12 to < 18 years of age<br>Patients will receive an IV loading regimen of isavuconazonium sulfate, which consists of a dose every 8 hours (+/- 2 hours) on days 1 and 2, followed by once daily IV maintenance dosing for up to 26 additional days (for a maximum of 28 days of dosing). | Drug: isavuconazonium sulfate - intravenous<br>* IV infusion<br>* Other names: Cresemba®;|
| Experimental: isavuconazonium sulfate oral cohort 4: 6 to < 12 years of age<br>Patients will receive a loading regimen of isavuconazonium sulfate by oral administration, comprising one dose every 8 hours (+/- 2 hours) on days 1 and 2 (a total of six doses), followed by once daily oral maintenance dosing for up to 26 additional days (for a maximum of 28 days of dosing). | Drug: isavuconazonium sulfate - oral<br>* Oral<br>* Other names: Cresemba®;|
| Experimental: isavuconazonium sulfate oral cohort 5: 12 to < 18 years of age<br>Patients will receive a loading regimen of isavuconazonium sulfate by oral administration, comprising one dose every 8 hours (+/- 2 hours) on days 1 and 2 (a total of six doses), followed by once daily oral maintenance dosing for up to 26 additional days (for a maximum of 28 days of dosing). | Drug: isavuconazonium sulfate - oral<br>* Oral<br>* Other names: Cresemba®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of isavuconazole in plasma: Cmax at steady state | Maximum concentration at steady state (Cmax) will be derived from the PK plasma samples collected. | Up to 7 days | 
| PK of isavuconazole in plasma: AUCtau | Area under the concentration time curve from the time of dosing to the start of next dosing interval at multiple dose conditions (AUCtau) will be derived from the PK plasma samples collected. | Up to 7 days | 
| PK of isavuconazole in plasma: tmax | Time of maximum concentration (tmax) will be derived from the PK plasma samples collected. | Up to 7 days | 
| PK of isavuconazole in plasma: Ctrough | Concentration - trough level (Ctrough) will be derived from the PK plasma samples collected. | Up to 28 days | 
| PK of isavuconazole in plasma: CL | Clearance (CL) will be model-derived. | Up to 28 days | 
| PK of isavuconazole in plasma: Vss | Volume of distribution at steady state (Vss) will be model-derived. | Up to 28 days | 
| PK of isavuconazole in plasma: AUCss | Area under the concentration-time curve at steady state (AUCss) will be model-derived. | Up to 28 days | 
| PK of isavuconazole in plasma: t 1/2 | Half-life (t1/2) will be model-derived. | Up to 28 days | 
| Safety assessed by nature, frequency and severity of Treatment Emergent Adverse Events (TEAEs) | A TEAE is defined as an Adverse Event (AE) observed after starting administration of the study drug through follow-up. AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Number of patients with TEAE's will be summarized. | Up to 58 days | 
| Number of patients with vital sign abnormalities and/or adverse events | An abnormality identified during a medical test (e.g. vital signs) should be defined as an AE only if the abnormality meets 1 of the following criteria: induces clinical signs or symptoms; requires active intervention; requires interruption or discontinuation of study drug; or the abnormality or test value is clinically significant. | Up to 28 days | 
| Number of patients with laboratory value abnormalities and/or adverse events | An abnormality identified during a medical test (e.g. laboratory parameter) should be defined as an AE only if the abnormality meets 1 of the following criteria: induces clinical signs or symptoms; requires active intervention; requires interruption or discontinuation of study drug; or the abnormality or test value is clinically significant. | Up to 28 days | 
| Safety assessed by routine 12- lead electrocardiogram (ECG) | Standard 12-lead ECG recordings will be used for the purposes of safety assessment. A 12-lead, resting ECG is to be recorded. Patients should remain supine for at least 5 minutes prior to all ECGs being performed. The results (normal, abnormal not clinically significant, abnormal clinically significant) are to be recorded. | Up to 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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invasive fungal disease, Cresemba®, Hematological malignancy, isavuconazonium sulfate, ASP9766, isavuconazole, pediatric population