Trial Information

A Phase II CT to Evaluate the Safety and Tolerability of Nebulised Amphotericin B Lipid Complex (ABELCET®) in the Prophylaxis of Invasive Pulmonary Aspergillosis During Prolonged Neutropenia in Paediatric Patients With Acute Leukaemia.

In recent years the incidence of IFI (invasive fungal infection) especially when caused by
filamentous fungi has increased in patients with haematological malignancies and there
exists an international consensus on diagnostic criteria. Despite diagnostic and therapeutic
progress, invasive aspergillosis remains a major clinical problem of haematological
patients, given the still high mortality rates and the huge economic cost of hospitalization
of patients, which is attributable to aspergillosis. In addition to the morbidity and
mortality rates, these infections interfere with the chemotherapy treatment plan with the
risk of compromising the outcome of the antileukemic treatment.

An infection caused by Aspergillus is usually acquired from inhalation of conidia. The lungs
are the primary site of infection in most patients. In the 1990's the administration of
aerosolised amphotericin B deoxycholate was evaluated as a prophylaxis of pulmonary fungal
infections. In a few uncontrolled studies inhaled amphotericin B deoxycholate showed some
benefit in haematological patients, however it was not effective in a large multicenter
study with neutropenic patients. Based on the outcome of that clinical trial, the use of
aerosolised amphotericin B deoxycholate in neutropenic patients was abandoned for nearly a
decade. During this time the use of azole agents as drugs of choice for antifungal
prophylaxis in high risk patients was consolidated. However, one of the main problems in the
use of triazoles with activity against filamentous fungi (itraconazole, voriconazole,
posaconazole) is drug-drug interactions due to their CYP3A4 inhibitory activity. One of the
most serious interactions is that which occurs with vincristine, used throughout the
treatment of acute lymphoblastic leukemia, and which has lead to reports of neurotoxicity
due to metabolic inhibition.

ABLC (Abelcet®) belongs to the group of polyenes with antifungal activity against a broad
spectrum of fungal species, including Aspergillus spp. Abelcet® is recommended for the
intravenous treatment of a broad spectrum of systemic fungal infections in adult patients.
Although it has a pediatric indication, there are numerous studies published regarding the
safety levels of Abelcet® administered intravenously in children.

There are experiences in adult haematological patients which look very promising. For
example, a non-comparative study in 27 subjects undergoing allogeneic HSCT (n=40) with
nonmyeloablative conditioning, showed good tolerability and achieved an effective
prophylaxis (IFI: 2.5%). The combined prophylactic regimen consisted of aerosolised ABLC
(Abelcet®) 50 mg once daily for 4 days, then once weekly for 13 weeks, and associated with
fluconazole 400 mg daily until day +100. The most relevant adverse events were not frequent
(cough, nausea, taste disturbance, vomiting [10/428 administrations (2.2%)]). Although some
patients showed a decrease in respiratory function measurements (5.2%), none required
treatment with bronchodilators or withdrawal from the study. Only three patients had proven
IFIs (and only one, a catheter-related case of disseminated fusariosis, occurred while
receiving the study medication).

Recently, another example, a randomised study in the Netherlands compared the prophylaxis
with liposomal amphotericin B versus placebo in neutropenic patients with a high IFI risk. A
total of 271 high-risk patients with haematological disease were studied during 407
neutropenic episodes. The prophylactic regimen consisted of fluconazole combined with
liposomal amphotericin B (Abelcet®) inhalation, two consecutive days per week (12.5 mg in 30
minutes, with a maximum of 12 inhalations per episode) using an adapted nebuliser delivery
system. According to the intent-to-treat (ITT) analysis, 18 of 132 patients (14%) in the
placebo group developed invasive aspergillosis (IPA), versus 6 of 139 patients (4%) in the
ABLC group (P=0.005). According to the on-treatment analysis (OT), 13 of 97 patients (13%)
in the placebo group versus 2 of 91 (2%) in the ABLC group developed IPA (P=0.007). This
experience has prompted a respected editorial to regard this method as an antifungal
prophylactic.

In conclusion, in the treatment of pediatric patients with haematological malignancies the
use of intensive chemotherapy is required, which is immunosuppressive and therefore
significantly increases the risk of IFI, especially filamentous fungi. IPA is associated
with high mortality (>50%) in those patients, making it imperative to adopt effective,
preventive, prophylactic measures. Drug interactions occur frequently with triazole
antifungal drugs; cases of clinically significant interactions with vincristine, an anchor
drug in the treatment of the majority of pediatric leukemia, are documented. On the other
hand, there are promising data from previous studies regarding the safety and efficacy of
the intravenous ABLC formulation (Abelcet®) in the treatment of pediatric patients with
fungal infections.

In this context, the working hypothesis proposed in this project is that the administration
of aerosolised ABLC for pediatric patients with acute leukemia treated with intensive
chemotherapy will be an effective alternative as a prophylaxis of pulmonary fungal
infections in these patients.

In the event that the working hypothesis is confirmed, aerosolised ABLC treatment would be
an effective, safe and reliable prophylactic option for IPA. It would offer an alternative
to the systemic administration of antifungal triazoles without affecting the antileukemic
treatment in pediatric patients with AL.