A Study of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients

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

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.

Study Overview

• Status: Completed
• Conditions: Hematological Malignancy
• Intervention / Treatment: Drug: isavuconazonium sulfate - intravenous; Drug: isavuconazonium sulfate - oral

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Long Beach, California, United States, 90806
      • Miller Children's Hospital
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92868
      • CHOC Children's Hospital of Orange County
  • Florida
    • Miami, Florida, United States, 33155
      • Nicklaus Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School Of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H Lurie Children's Hospital of Chicago
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Kansas City
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • University Hospital of Cleveland
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • The Children's Hospital at TriStar Centennial Medical Center
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: isavuconazonium sulfate IV cohort 1: 1 to < 6 years of age; 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; IV infusion; Other Names: Cresemba®
Experimental: isavuconazonium sulfate IV cohort 2: 6 to < 12 years of age; 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; IV infusion; Other Names: Cresemba®
Experimental: isavuconazonium sulfate IV cohort 3: 12 to < 18 years of age; 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; IV infusion; Other Names: Cresemba®
Experimental: isavuconazonium sulfate oral cohort 4: 6 to < 12 years of age; 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; Oral; Other Names: Cresemba®
Experimental: isavuconazonium sulfate oral cohort 5: 12 to < 18 years of age; 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; Oral; Other Names: Cresemba®

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: Basilea Pharmaceutica International Ltd
• Investigators: Study Director: Senior Medical Director, Astellas Pharma Global Development, Inc.

Publications and helpful links

General Publications

• Arrieta AC, Neely M, Day JC, Rheingold SR, Sue PK, Muller WJ, Danziger-Isakov LA, Chu J, Yildirim I, McComsey GA, Frangoul HA, Chen TK, Statler VA, Steinbach WJ, Yin DE, Hamed K, Jones ME, Lademacher C, Desai A, Micklus K, Phillips DL, Kovanda LL, Walsh TJ. Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients. Antimicrob Agents Chemother. 2021 Jul 16;65(8):e0029021. doi: 10.1128/AAC.00290-21. Epub 2021 Jul 16.

Helpful Links

• Link to results and other applicable study documents on the Astellas Clinical Trials website
• Link to plain language summary of the study on the Trial Results Summaries website

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2017
• Primary Completion (Actual): July 5, 2019
• Study Completion (Actual): July 5, 2019

Study Registration Dates

• First Submitted: August 3, 2017
• First Submitted That Met QC Criteria: August 3, 2017
• First Posted (Actual): August 7, 2017

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: pediatric population; ASP9766; isavuconazole; Hematological malignancy; isavuconazonium sulfate; invasive fungal disease; Cresemba®
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms; Anti-Infective Agents; Antifungal Agents; Isavuconazole
• Other Study ID Numbers: 9766-CL-0046

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No