In a phase III trial, posaconazole (Noxafil Oral Suspension), an investigational broad-spectrum triazole antifungal, significantly reduced the incidence of serious invasive fungal infections (IFIs) and of aspergillosis, and demonstrated a survival benefit, compared with standard azole antifungal treatment in high-risk neutropenic patients undergoing intensive chemotherapy.
ATLANTAIn a phase III trial, posaconazole (Noxafil Oral Suspension), an investigational broad-spectrum triazole antifungal, significantly reduced the incidence of serious invasive fungal infections (IFIs) and of aspergillosis, and demonstrated a survival benefit, compared with standard azole antifungal treatment in high-risk neutropenic patients undergoing intensive chemotherapy. Lead investigator Oliver Cornely, MD, of the University of Cologne, presented the results at the 47th Annual Meeting of the American Society of Hematology (abstract 1844).
In this randomized, evaluator-blinded, active-controlled, multicenter study, sponsored by Schering-Plough Corporation, prophylaxis with posaconazole was compared against treatment with the standard azoles itraconazole and fluconazole for prevention of IFIs in patients who had a new diagnosis or first relapse of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) and were neutropenic as a result of intensive chemotherapy.
Dr. Cornely noted, "These infections are increasingly caused by molds that are both difficult to diagnose and treat. . . . The results of this study demonstrated that [posaconazole] prophylaxis was associated with significant overall and IFI-related survival in these patients, compared to standard azole prophylaxis."
Patients were randomized to receive posaconazole at a dose of 200 mg three times daily (n = 304) or oral standard azoles, either fluconazole oral suspension at 400 mg daily (n = 240) or itraconazole oral solution at a dose of 200 mg twice daily (n = 58), with each cycle of chemotherapy until complete remission or for a maximum of 12 weeks. The primary efficacy endpoint of the study was incidence of proven and probable IFIs during the treatment phase (7 days after last dose) as evaluated by a blinded expert panel based on EORTC (European Organization for Research and Treatment of Cancer)/MSG (Mycoses Study Group) criteria. Investigators also compared the incidence of aspergillosis during treatment and the incidence of IFIs 100 days after randomization.
Significantly Fewer IFIs
The number of proven and probable IFIs during treatment was significantly lower with posaconazole prophylaxis than with the standard azoles (7 vs 25; P = .0009). Posaconazole also significantly reduced the number of Aspergillus infections during treatment (2 vs 20; P = .0001) and the number of all invasive fungal infections within 100 days post-randomization (14 vs 33; P = .0031).
Overall all-cause mortality was 49 (16%) vs 67 (22%) (P = .048) for patients in the posaconazole and standard-azole arms, respectively. Posaconazole also demonstrated a significant survival benefit vs standard azole therapy in an analysis of time to death (all-cause mortality) within 100 days post-randomization (P = .035).
Safety and tolerability of posaconazole were comparable to fluconazole, and the investigators noted a similar incidence of treatment-related adverse events and patient discontinuations for these groups. Gastrointestinal events were the most common adverse events occurring in both treatment groups.
Posaconazole was approved in the European Union in October 2005 for treatment of certain serious IFIs in adult patients who are intolerant of standard antifungals or have disease that is refractory to certain commonly used antifungal agents, and the agent was recently launched in Germany. In June 2005, the FDA issued an approvable letter to Schering-Plough in response to an application for posaconazole to treat refractory IFIs.