Prompt central venous catheter (CVC) removal is often recommended in candidemic patients [1,2]. To investigate further, we evaluated relationships between CVC status and 28-day and 42-day survival post-treatment initiation, overall treatment success, and time to mycological eradication.

We describe herein 98 hematopoietic stem cell transplant (HSCT) recipients with invasive aspergillosis (IA) (refractory in 83) who received micafungin either alone (8 patients) or in combination with other licensed antifungal therapies (OLAT) (90 patients). Of the 8 monotherapy patients, 4 were failing OLAT, received de novo micafungin, or were intolerant to prior OLAT (2 patients each). Of the 90 patients treated with combination, 7 had de novo IA and 83 had refractory infection. Most patients (81) had pulmonary IA, 42 (43%) had graft-versus-host disease (GVHD), and 26 (27%) were neutropenic (absolute neutrophil count <500 cells/mm(3)) at onset of treatment. Successful response was seen in 25/98 (26%); an additional 12 patients achieved stable disease. Response was seen in 2/9 (22%) in de novo treatment, 21/87 (24%) in refractory patients, and 2/2 (100%) in toxicity failure patients. Additionally, response was seen in 22 of the 90 (24%) patients treated with combination therapy, and in 3 of 8 (38%) patients who were treated with micafungin alone. No significant differences in responses were found based on type of HSCT, GVHD status, site of IA, or Aspergillus species, and no significant toxicity was seen. Micafungin was well tolerated, even at high doses, and is a reasonable option for treatment of IA in this high-risk patient population.

We assessed the pharmacokinetics and interactions of steady-state micafungin (Mycamine) or placebo with steady-state voriconazole in 35 volunteers. The 90% confidence intervals around the least-squares mean ratios for micafungin pharmacokinetic parameters and placebo-corrected voriconazole pharmacokinetic parameters were within the 80%-to-125% limits, indicating an absence of drug interaction.

A.J. ULLMANN, J. DE WAELE, R. BETTS, C. ROTSTEIN, M. NUCCI, L. KOVANDA, C. WU, D. BUELL, H. DIEKMANN, S. KOBLINGER, O.A. CORNELY Klinikum Johannes Gutenberg-Universitat, Mainz, Germany, Ghent University, Ghent, Belgium, University of Rochester, Rochester, NY, USA, Hamilton HS, Hamilton, Ontario, Canada, Federal University, Rio de Janeiro, Brazil, Astellas Pharma US, Deerfield, IL, USA, Astellas Pharma GmbH, Munich, Germany, University of Cologne, Koln, Germany

3014 Background: Survivin is one of the family of inhibitor of apoptosis proteins (IAP) that suppresses apoptosis through inhibition of caspases and procaspases. Survivin is selectively expressed in most solid tumors but not normal tissues. In a PC-3 cell model YM155 inhibited survivin mRNA transcription and survivin protein expression and showed potent (nM) anti-proliferative activity in preclinical models including tumor regressions. Methods: The objectives were to determine the maximum tolerated dose (MTD) of 168 hour continuous infusion of YM155 every 3 weeks, to evaluate toxicity, characterize the pharmacokinetics and observe anti-tumor activity. Standard 3+3 dose escalation scheme was utilized. Additional pts were added to fully characterize toxicities at the MTD. Pharmacokinetic sampling was performed during cycles 1 and 2. Results: 41 pts (M/F: 31/10, median age 61, range 28–78) with performance status of 0–2 were enrolled into 4 dose cohorts [1.8 mg/m2/day (N = 8), 3.6 (6), 6.0 (2) and 4.8 (25)]. Most common tumor types were prostate (9), NHL (5), and colorectal (5). 2/2 pts experienced DLTs at 6.0 (renal tubular necrosis with grade 3 mucositis and increased serum creatinine), thus the MTD was 4.8 mg/m2/day. The most frequent AEs were: pyrexia, arthralgia, nausea, fatigue and diarrhea. The most common grade 3 or 4 drug related AEs were: mucosal inflammation (N = 2, 4.9%) and increased INR (N = 2, 4.9%). At MTD, the median clearance was 47 L/hr with a median steady state concentration of 7.5 ng/mL and a median terminal half-life of 22 hours. Two pts with chemotherapy refractory intermediate grade NHL had marked reduction of lymph nodes including one that was durable (PR reviewed independently). This pt went onto BMT and was in remission at the time of this submission. Two HRPC pts exhibited PSA response (> 50% reduction). Conclusions: YM 155, the first survivin inhibitor, was well tolerated, had a MTD of 4.8 mg/m2/day × 7 days and exhibited provocative anti-tumor activity in 4 pts that warrant broad phase II evaluation. No significant financial relationships to disclose.

Melanoma, the most aggressive form of skin cancer, results from the malignant transformation of melanocytes located in the basement membrane separating the epidermal and dermal skin compartments. Cutaneous melanoma is often initiated by solar ultraviolet radiation (UVR)-induced mutations. Melanocytes intimately interact with keratinocytes, which provide growth factors and melanocortin peptides acting as paracrine regulators of proliferation and differentiation. Keratinocyte-derived melanocortins activate melanocortin-1 receptor (MC1R) to protect melanocytes from the carcinogenic effect of UVR. Accordingly, MC1R is a major determinant of susceptibility to melanoma. Despite extensive phenotypic heterogeneity and high mutation loads, the molecular basis of melanomagenesis and the molecules mediating the crosstalk between melanoma and stromal cells are relatively well understood. Mutations of intracellular effectors of receptor tyrosine kinase (RTK) signalling, notably NRAS and BRAF, are major driver events more frequent than mutations in RTKs. Nevertheless, melanomas often display aberrant signalling from RTKs such as KIT, ERRB1-4, FGFR, MET and PDGFR, which contribute to disease progression and resistance to targeted therapies. Progress has also been made to unravel the role of the tumour secretome in preparing the metastatic niche. However, key aspects of the melanoma-stroma interplay, such as the molecular determinants of dormancy, remain poorly understood.

ABSTRACT In this dose escalation study, 74 adult cancer patients undergoing bone marrow or peripheral blood stem cell transplantation received fluconazole (400 mg/day) and either normal saline (control) (12 subjects) or micafungin (12.5 to 200 mg/day) (62 subjects) for up to 4 weeks. The maximum tolerated dose (MTD) of micafungin was not reached, based on the development of Southwest Oncology Group criteria for grade 3 toxicity; drug-related toxicities were rare. Commonly occurring adverse events considered related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rash (4.1%), and rash (4.1%). Pharmacokinetic profiles for micafungin on days 1 and 7 were similar. The mean half-life was approximately 13 h, with little variance after repeated or increasing doses. Mean maximum concentrations of the drug in serum and areas under the concentration-time curve from 0 to 24 h were approximately proportional to dose. There was no clinical or kinetic evidence of interaction between micafungin and fluconazole. Five of 12 patients (42%) in the control group and 14 of 62 (23%) in the micafungin-plus-fluconazole groups had a suspected fungal infection during treatment which resulted in empirical treatment with amphotericin B. The combination of micafungin and fluconazole was found to be safe in this high-risk patient population. The MTD of micafungin was not reached even at doses up to 200 mg/day for 4 weeks. The pharmacokinetic profile of micafungin in adult cancer patients with blood or marrow transplants is consistent with the profile in healthy volunteers, and the area under the curve is proportional to dose.

Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol‐O‐methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance <30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single‐dose micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed micafungin concentration‐time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 ± 19 μg•h/mL vs 125.9 ± 26.4 μg•h/mL, P = .03), although there was no difference in micafungin weight‐adjusted clearance (10.9 ± 1.7 mL/h/kg vs 9.8 ± 1.8 mL/h/kg, P = .2). The difference in area under the concentration‐time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter micafungin pharmacokinetics.

SummaryAim: To determine efficacy and safety of intravenous micafungin vs. intravenous fluconazole in the treatment of oesophageal candidiasis.Methods: A total of 523 patients ≥16 years with documented oesophageal candidiasis were randomized (1:1) in this controlled, non‐inferiority study to receive either micafungin (150 mg/day) or fluconazole (200 mg/day). Response was evaluated clinically and endoscopically. Post‐treatment assessments were performed at 2 and 4 weeks after discontinuation of therapy.Results: Median duration of therapy was 14 days. For the primary end‐point of endoscopic cure, treatment difference was −0.3% (micafungin 87.7%, fluconazole 88.0%). Documented persistent invasive disease at the end of therapy was reported in 2.7% and 3.9% of patients, respectively. Both 84.8% of micafungin and 88.7% of fluconazole patients remained recurrence free at 4‐weeks post‐treatment. The overall therapeutic response rate was 87.3% for micafungin and 87.2% for fluconazole. The incidence of drug‐related adverse events was 27.7% for micafungin and 21.3% for fluconazole. Six (2.3%) micafungin‐ and two (0.8%) fluconazole‐treated patients discontinued therapy; rash was the most common event leading to discontinuation.Conclusion: Intravenous micafungin (150 mg daily) is well tolerated and as efficacious as intravenous fluconazole (200 mg daily) in the primary treatment of oesophageal candidiasis, achieving high rates of clinical and endoscopic cure.

AIM:To determine the minimum effective dose and safety of micafungin in the treatment of HIV-related oesophageal candidiasis.METHOD:A total of 120 patients were enrolled in this open label study of the effects of daily 1 h infusions of micafungin on endoscopically proven fungal oesophagitis. Patients were randomly assigned to receive 12.5, 25, 50, 75 and 100 mg of micafungin daily. Response was evaluated clinically and endoscopically.RESULTS:The protocol defined minimum effective dose of micafungin was 12.5 mg. The percentage of patients experiencing clearing of physical signs and symptoms showed a dose-response relationship and reached 94.7% in the 100 mg dose group. All patients in the 50, 75 and 100 mg dose groups achieved an endoscopically verified improvement in oesophagitis. Adverse effects of micafungin were generally mild and not dose-related. No serious renal, hepatic or drug-related infusion reactions were encountered.CONCLUSION:Micafungin was found to be effective, well-tolerated and safe. The minimum effective dose was found to be 12.5 mg and a significant linear trend in the successful treatment of oesophageal candidiasis was observed across the doses used with 75 and 100 mg dose levels achieving high rates of clinical and endoscopic cure.

We investigated the clinical characteristics and treatment of patients with a distinctive triad of acute infusion-related reactions (AIRRs) to liposomal amphotericin B (L-AMB) via single-center and multicenter analyses. AIRRs occurred alone or in combination within 1 of 3 symptom complexes: (1) chest pain, dyspnea, and hypoxia; (2) severe abdomen, flank, or leg pain; and (3) flushing and urticaria. The frequency of AIRRs in the single-center analysis increased over time. Most AIRRs (86%) occurred within the first 5 min of infusion. All patients experienced rapid resolution of symptoms after intravenous diphenhydramine was administered. The multicenter analysis demonstrated a mean overall frequency of 20% (range, 0%-100%) of AIRRs among 64 centers. A triad of severe AIRRs to L-AMB may occur in some centers; most of these reactions may be effectively managed by diphenhydramine administration and interruption of L-AMB infusion.

After the transplantation of unmodified marrow from human leukocyte antigen-matched unrelated donors receiving cyclosporine (CSP) and methotrexate (MTX), the incidence of acute graft-versus-host disease (GVHD) is greater than 75%. Tacrolimus is a macrolide compound that, in previous preclinical and clinical studies, was effective in combination with MTX for the prevention of acute GVHD. Between March 1995 and September 1996, 180 patients were randomized in a phase 3, open-label, multicenter study to determine whether tacrolimus combined with a short course of MTX (n = 90), more than CSP and a short course of MTX (n = 90), would reduce the incidence of acute GVHD after marrow transplantation from unrelated donors. There was a significant trend toward decreased severity of acute GVHD across all grades (P =.005). Based on the Kaplan-Meier estimate, the probability of grade II-IV acute GVHD in the tacrolimus group (56%) was significantly lower than in the CSP group (74%; P =.0002). Use of glucocorticoids for the management of GVHD was significantly lower with tacrolimus than with CSP (65% vs 81%, respectively; P =. 019). The number of patients requiring dialysis in the first 100 days was similar (tacrolimus, 9; CSP, 8). Overall and relapse-free survival rates for the tacrolimus and CSP arms at 2 years was 54% versus 50% (P =.46) and 47% versus 42% (P =.58), respectively. The combination of tacrolimus and MTX after unrelated donor marrow transplantation significantly decreased the risk for acute GVHD than did the combination of CSP and MTX, with no significant increase in toxicity, infections, or leukemia relapse.

Recent increases in the number of potentially life-threatening systemic fungal infections in immunocompromised patients have made the development of improved antifungal therapies more urgent. Current treatments, including amphotericin B and the azoles, suffer from a lack of broad-spectrum fungicidal action and/or undesirable toxicities. In this review, two novel but different antifungal preparations are compared to illustrate the diversity in current approaches to antifungal therapy. A semi-synthetic echinocandin analog (FK463) is the result of efforts to develop compounds that inhibit specific biochemical targets found in fungal cells. A liposomal formulation of amphotericin B (AmBisome) demonstrates the ability of advanced drug delivery systems to improve the safety profile of a toxic, but otherwise effective drug.

Amphotericin B has been the mainstay of systemic antifungal therapy for over 30 years, despite its serious side-effects, and, although numerous alternative antifungal agents have been developed, none to date has matched the efficacy of amphotericin B. However, modern drug delivery technology has improved the safety of amphotericin B by incorporating it into lipid-based delivery systems, including liposomes. Three such formulations, based on the natural affinity of amphotericin B for lipids, are currently marketed. All increase the therapeutic index of amphotericin B, thereby allowing more aggressive treatment than is possible with the conventional product. However, they differ in structure, side-effect profiles and evidence of proven efficacy as discussed in this review.