Invasive Pulmonary Aspergillosis Clinical Trial
Official title:
A Phase II Trial 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
The trial evaluates the overall tolerability of the drug and the efficacy of aerosolised amphotericin B as a lipid complex (ABLC) for primary prophylaxis of invasive pulmonary aspergillosis (IPA) in pediatric patients with acute leukemia undergoing intensive chemotherapy.
In recent years the incidence of invasive fungal infection (IFI) 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.
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. The active component of ABELCET®,
amphotericin B, acts by binding to sterols in the cell membrane of susceptible fungi, with a
resultant change in the permeability of the membrane. Mammalian cell membranes also contain
sterols, and damage to human cells is believed to occur through the same mechanism of action.
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 and in haematological adults patients which look very promising. 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 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.
If the working hypothesis is confirmed, the 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.
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