A Randomised, Stratified, Open Label, Phase II Pilot Study on the Safety of a Daily, Intermittent, or Weekly Administration of 1, 3 or 10mg/kg of AmBisome® in Antifungal Primary Prophylaxis of High-Risk Patients With Acute Myeloid Leukaemia
Invasive Fungal Infections (IFI)are a significant cause of death in patients with acute
leukaemia who are undergoing chemotherapy. This is despite improvements in antifungal
therapy for the treatment of IFI. The major reason for this is that the current standard
diagnostic tests of culture and biopsy lack the ability to make a diagnosis, either early or
accurately. Thus other strategies such as the use of prophylaxis are needed. Several
antifungal agents have been trialled as prophylaxis but all have disadvantages that limit
Liposomal amphotericin B(LAB) is a broad spectrum antifungal agent that kills fungal cells.
When given in high doses intermittently it supersaturates the liver and the overspill into
the bloodstream is absorbed by tissues such as lung, brain and kidneys (i.e. sites where IFI
are likely to occur). This effect has been shown in a number of animal and laboratory
test-tube studies to reduce fungal burden, improve survival and maintain adequate levels of
the drug in between doses. However no intermittent high-dose prophylaxis study has been done
in humans. Thus before we proceed to a randomised controlled clinical trial of the efficacy
of intermittent high-dose LAB compared with another antifungal agent it is necessary to
determine in a phase 2 study which of 2 intermittent dosing LAB regimens (i.e. 3mg/kg three
times a week or 10mg/kg once a week) administered during the neutropenic phase of
induction-consolidation chemotherapy for treatment of acute leukaemia is safest and best
tolerated compared to the standard dosing regimen of 1mg/kg daily of LAB.
Males and females aged >18 years who are undergoing intensive combination chemotherapy for
acute leukaemia will be randomised 1:1:1 to either 1mg/kg daily; 3mg/kg 3 times a week or
10mg/kg once weekly of intravenous liposomal amphotericin B. The 3 arms will be compared for
the safety of the 3 dosing regimens.
Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention
Safety as defined by the incidence of all adverse events occurring by the completion of each trial prophylaxis course.
C. Orla Morrissey, MB, BCh, FRACP
The Alfred Hospital, Level 2 Burnet Institute, Commercial Rd., Melbourne, 3004, Victoria, Australia
Australia: Department of Health and Ageing Therapeutic Goods Administration