TARGETED TREATMENT

George R Thompson, III, MD: Any thoughts on some of the newer pediatric data for mold-active triazole agents?

Isavuconazole for Invasive Mold Infections

Antonio Arrieta, MD: Yes, there is a recently completed study of posaconazole for invasive aspergillosis in pediatrics.27A few years ago, I was part of a team that conducted a pharmacokinetic (PK) study evaluating pediatric dosing of isavuconazole that was used to develop a dosing strategy.28 The findings of this Phase 1 study supported further investigation of the 10 mg/kg dosing strategy, which was explored in the recent Phase 2 pediatric study of isavuconazole for the treatment of Aspergillus spp. and Mucor infections.29 That has allowed us to have more insight into these therapies.

George R Thompson, III, MD: Can you tell me more about that phase 2 study? What kind of patients were enrolled in that study?

Antonio Arrieta, MD: This trial was a phase 2, non-comparative open-label trial looking at isavuconazole for the treatment of invasive aspergillosis and/or invasive mucormycosis in pediatric patients aged 1 to <18 years of age.29 The study included 31 patients, 12 had proven or probable invasive aspergillosis, which is a pretty high number, particularly with the understanding that we used the 2008 criteria from the European Organisation for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) for diagnosis, in which PCR and/or NGS could not be used to elevate their diagnosis from possible invasive fungal disease to proven-probable aspergillosis. There was 1 mucormycosis patient; the rest had either possible invasive fungal disease (IFD, n = 16) or other IFD (n = 2). The demographic information from the study is shown in Table 2. As you can see, malignancy was the most common underlying condition in this population.

Table 2. Patient characteristics at baseline in the isavuconazole study, full analysis set.29

1ALL, acute lymphoblastic leukemia; AML, acute myeloblastic leukemia (includes relapsed disease); B-LL, B-cell lymphoblastic leukemia/lymphoma; MDS to AML, myelodysplastic syndrome transformed to AML; NHL, non-Hodgkin lymphoma.
2Two of the patients with possible IFD was subsequently determined by the independent adjudication committee as not meeting the EORTC/MSG 2008 criteria (13) for possible IFD.
3An investigator assessment of IFD diagnosis was used; diagnostic tests to assess whether the disease was “proven” or “probable” IA or IM, according to the EORTC/MSG 2008 criteria, were completed within 10 days after the first dose of the study drug.
4Other IFDs were defined as IFDs assessed not to be IA or IM.
5Medulloblastoma.
6Includes systemic lupus erythematosus, solid organ transplant, multi-visceral transplant, central venous access (congenital ileal atresia), cystic adenomatoid malformation (congenital), Fanconi’s anemia, primary pulmonary hypertension, and aplastic anemia.

The dosing for this study was supported by evidence from SECURE, which was a controlled trial in adult patients with IFI and, as I mentioned earlier, the Phase 1 pediatric study that looked at pharmacokinetic parameters and safety data. I’ll speak more to that in a bit in terms of the pharmacokinetic pediatric drug exposure data. Patients received a loading regimen of 10 mg/kg isavuconazonium sulfate (equivalent to 5.4 mg/kg isavuconazole), up to a maximum of 372 mg of isavuconazonium sulfate (equivalent to 200 mg isavuconazole) every 8 h (±2 h) for six total doses over days 1 and 2. A once-daily maintenance dose of 10 mg/kg isavuconazonium sulfate (up to a maximum of 372 mg) was then administered for up to 84 days (IA) or 180 days (IM), or until a successful response was achieved (a combination of mycological, clinical, and radiologic criteria defined in supplemental methods), whichever occurred first (Figure 4). Subjects were followed for up to 60 days posttreatment. The primary clinical outcome was an all-cause case-fatality rate through day 42. The primary safety outcome was treatment-emergent adverse events (TEAEs). TEAEs were identified by continuous recording of adverse events (AEs). Secondary outcomes included all-cause fatality through day 84 and end of treatment (EOT), overall response, and pharmacokinetic outcomes.29

Figure 4. Study design of the phase 2 isavuconazole study.29

All patients were assigned to open-label treatment via IV or oral route at the discretion of the investigator. Reproduced from the open-source article Segers H, Deville JG, Muller WJ, et al. Safety, outcomes, and pharmacokinetics of isavuconazole as a treatment for invasive fungal diseases in pediatric patients: a non-comparative phase 2 trial. Antimicrob Agents Chemother. 2024;68(12):e0048424. doi:10.1128/aac.00484-24, licensed by Creative Commons 4.0. FAS = full analysis set; EOT = end of treatment; IA = invasive aspergillosis; IM = invasive mucormycosis; IV = intravenous; PKAS = pharmacokinetic analysis set; SAF = safety analysis set.

The all-cause case fatality rate is shown in Figure 5. The all-cause case fatality rate through day 42 was 6.5% (2/31). One patient died of progression of IFD 5 days after isavuconazole was discontinued, and another died of septic shock 20 days after isavuconazole was discontinued. One additional death, attributed to cardiovascular collapse, occurred between days 42 and 84, resulting in a total of three deaths occurring during follow-up (9.7%, 3/31). The duration of time between isavuconazole discontinuation and death was 23 days for the patient with cardiovascular collapse.29

Figure 5. Isavuconazole all-cause case fatality rate.29

EOT = end of treatment, up to 84 (IA) or 180 days (IM). Not all patients received drug up to those time periods. All deaths occurred after isavuconazole discontinuation and were not considered related to treatment. IFD other = fusariosis and coccidioidomycosis; IA = invasive aspergillosis; IM = invasive mucormycosis; IFD = invasive fungal disease. Adapted from Segers et al. 2024.

George R Thompson, III, MD: How were the outcomes adjudicated, and what were the responses? I think typically we’re used to seeing the day-42 and day-84 outcomes, but what did those look like in this isavuconazole trial? How are the outcomes determined for the overall response rates?

Antonio Arrieta, MD: We used the same timing for evaluation. There was an evaluation committee that looked at the adjudication of success of treatment, which was defined based on a combination of clinical, mycological, and radiologic criteria (as outlined in the supplemental information). There were measurements at days 42, 84, and EOT. Using this measure, almost 67% (or two thirds) of patients with proven or probable invasive aspergillosis had a successful response at EOT.29

George R Thompson, III, MD: That’s helpful. In the adults, which I don’t want to extrapolate totally to pediatrics, we use a fair amount of isavuconazole due to its safety profile. What are some of the side effects that you see clinically?

Antonio Arrieta, MD: So, we have had adult literature suggesting that isavuconazole is a safer agent than the other azoles currently available. For example, the Phase 3 SECURE study conducted in adults showed that isavuconazole was non-inferior to voriconazole in terms of efficacy, but there were significant differences in the safety profile.30 That study found that isavuconazole, as compared with voriconazole, had statistically significantly fewer treatment-emergent hepatobiliary side effects as well as skin cutaneous side effects, which are common in pediatrics and often limiting adverse events. Additionally, isavuconazole was associated with statistically significantly fewer eye disorders.

We found that the safety profile in pediatrics (including serious adverse events as well as those leading to discontinuation) was similar to that in the adult population. Treatment-emergent adverse events (TEAEs) occurred in 93.5% (29/31) of patients (Table 3). Nine participants reported a total of 24 treatment-related TEAEs (reported in the supplemental information) (Table 4). Drug-related TEAEs led to discontinuation in 6.5% (2/31) of patients (Table 3). One was for an injection site reaction, and one was for hypotension. The majority (23/24) of drug-related TEAEs were rated as mild or moderate (95.8%). Only one drug-related TEAE, hypotension, was severe in intensity.

Table 3. Overview of TEAEs in the Phase II Study.29

Adapted from Segers et al. 2024.

Table 4. Drug-related TEAEs in the Phase II Study.29


Adapted from Segers et al. 2024.

The most common TEAEs were, for example, pyrexia (occurring in 29.0% of patients, 9/31), diarrhea (25.8%, 8/31), and vomiting (22.6%, 7/31). Two (6.5%; 2/31) patients had elevations in alanine aminotransferase(ALT)/aspartate aminotransferase (AST) levels >10 times the upper limit of normal (ULN). There were three patients who had elevated ALT and/or aspartate aminotransferase (AST) >3× ULN and total bilirubin >2× ULN; however, for each patient, there were other significant or confounding factors affecting liver function tests in these patients. In general, there were no trends in liver function abnormalities.

TABLE OF CONTENTS

Faculty

George R. Thompson, III, MD

Professor of Medicine
University of California, Davis, School of Medicine
Sacramento, California

Antonio C. Arrieta, MD

Division Chief
Pediatric Infectious Diseases
Children’s Hospital of Orange County (CHOC)
Orange, California

MyCARE thanks Astellas for sponsoring this activity.

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