Safety, outcomes, and pharmacokinetics of isavuconazole as a treatment for invasive fungal diseases in pediatric patients: a non-comparative phase 2 trial

Abstract

Invasive aspergillosis (IA) and mucormycosis (IM) cause significant morbidity and mortality in immunocompromised and/or hospitalized patients. Isavuconazonium sulfate, a prodrug of the antifungal triazole isavuconazole, has been approved for treatment of IA and IM in adults; and was recently approved in children. This study describes the outcomes, safety, and pharmacokinetics of isavuconazole for the treatment of proven, probable, or possible IA or IM in children. In this phase 2, open-label, non-comparative study, patients aged 1 to <18 years with at least possible invasive mold disease were enrolled across 10 centers in the US, Spain, and Belgium from 2019 to 2022. Patients received 10 mg/kg isavuconazonium sulfate daily (maximum 372 mg; equivalent to 5.4 mg/kg or 200 mg isavuconazole) for up to 84 (IA) or 180 days (IM). Outcomes included rates of all-cause case fatality, overall response, treatment-emergent adverse events (TEAEs), and pharmacokinetics. Of 31 patients enrolled, 61.3% were 1-<12 years old; 58.1% had underlying hematologic malignancies. The successful overall response rate at the end of treatment was 54.8%. Day 42 all-cause case fatality was 6.5%; 93.5% experienced TEAEs, and two patients discontinued treatment due to drug-related TEAEs. Dosing at 10 mg/kg (maximum dose: 372 mg) met the pre-defined exposure threshold of above the 25th percentile for the area under the concentration-time curve (≥60 mg·h/L). Simulated doses of 15 mg/kg improved drug exposures in patients aged 1-<3 years. Isavuconazole was well tolerated in children, with exposure consistent with adult studies. Successful response was documented in 54.8% of patients.CLINICAL TRIALSThis study is registered at ClinicalTrials.gov as NCT03816176.

Keywords: invasive fungal diseases; isavuconazole; pediatrics.

Fig 1

Study design. All patients were assigned to open-label treatment via IV or oral route at the discretion of the investigator. FAS, full analysis set; EOT, end of treatment; IA, invasive aspergillus; IM, invasive mucormycosis; IV, intravenous; PKAS, pharmacokinetic analysis set; SAF, safety analysis set.

Fig 2

Adjudication committee-assessed overall response (FAS). AC, adjudication committee; FAS, full analysis set; IA, invasive aspergillosis; IFD: invasive fungal disease; IM, invasive mucormycosis; EOT, end of treatment. Not evaluable includes those assessments that could not be made due to lack of data and no assessment performed by the AC because the patient did not reach the assessment day (discontinued treatment prior to either day 42 or day 84 of therapy). The overall response was based on a composite of clinical, mycological, and radiological responses with success criteria assessed. At EOT, the only patient in the IM subgroup was assessed as failure (due to progression) and both patients in the other IFD subgroup were considered “not evaluable” for overall response. ^†Proven/probable.

Fig 3

Comparison of AUC_ss values by age group versus previous adult studies. AUC₂₄, the area under the concentration-time curve over 24 h; Boxes represent the median and 25th and 75th percentiles, whiskers represent the range of maximum and minimum values within 1.5× the interquartile range, and outliers are shown as­ circle­s. The dashed blue line is the mean AUC_ss (101 mg·h/L) from the SECURE study (9). The dashed green line is the minimum (233 mg·h/L) AUC₂₄ value in a high-dose adult study (12, 14) (1,116 mg) with increased toxicity and represents the upper limit of the target exposure range for pediatric patients. The dashed orange line is the lower limit of the targeted exposure value (AUC_ss: 60 mg·h/L), which is taken from the 25th percentile of observed exposures in adults from the phase 3 SECURE trial (9, 12). *Overall population based on the combined patient populations from this study and the previous phase 1 study population (12).