Dose Escalation of Caspofungin for Invasive Aspergillosis - A Phase II Trial

Treatment of invasive aspergillosis (IA) fails in up to 50% of all cases and the mortality rate is at least 30%. Antifungal combination treatment has not been proven to be beneficial and dose escalation with liposomal amphotericin B did not improve outcome. New approaches are needed for patients with severe immunosuppression.

Escalating high dosages of caspofungin were investigated in IA defined according to modified EORTC/MSG criteria. The tested cohort of patients received 70mg, 100mg, 150mg or 200mg QD, 8 patients each were to receive caspofungin first-line treatment for proven/probable IA for up to 28 days. Dose limiting toxicity was defined as 2 of 8 patients in the same cohort with the same grade ≥4 non-hematological treatment-related adverse event (TRAE), or 4 of 8 patients with a grade ≥3 non-hematological TRAE. If no dose-limiting toxicity was reached, 12 additional patients were to be enrolled in the 200mg cohort. Patients unevaluable for toxicity or pharmacokinetic analysis were replaced.

A total of 46 patients were treated in the 4 cohorts (9, 8, 9, 20 pts). IA was proven in 2.2% and probable in 97.8%. Patient characteristics were as follows: Median age 61 years (min 18.3, max 73.7); 21/46 (45.7%) female. Underlying disease distribution was: AML 50%, ALL 8.7%, lymphoma 19.6%, chronic lymphocytic leukaemia 10.9%, other 10.9%. Median duration of treatment was 24.5 days. Two (4.3%) patients with treatment durations ≤5 days were replaced for pharmacokinetic analysis, but evaluated for safety and efficacy. No dose-limiting toxicity was found by investigator or DSMB assessment. At end of treatment (EOT) complete plus partial response was achieved in the 4 cohorts in 4/9, 3/8, 6/9, 12/20 patients, i.e. 25/46 (54.3%) of the total population. Stable disease was achieved in 4 patients (8.7%), 17 (37%) patients failed treatment. Overall survival at 12 weeks was 76.1%. After a 12 week follow-up attributable mortality was 8.7%. Death due to malignancy occurred in 10.9%, to sepsis in 8.7%.

In the first-line treatment of proven or probable invasive aspergillosis no dose-limiting toxicity of caspofungin at doses up to 200 mg QD was found. Complete plus partial response rates at EOT were 54.3% after dose-escalated caspofungin treatment, and thus in the range of the success rates previously reported with voriconazole and liposomal amphotericin B. Twelve weeks after start of treatment the 23.9% overall mortality rate was lower than that found in the literature.

Cornely: MSD: Consultancy, Honoraria. Vehreschild: MSD: Honoraria. Rüping: MSD: Honoraria. Silling: MSD: Membership on an entity's Board of Directors or advisory committees. Lehrnbecher: MSD: Membership on an entity's Board of Directors or advisory committees. Ullmann: MSD: Honoraria. Groll: MSD: Membership on an entity's Board of Directors or advisory committees. Karthaus: MSD: Membership on an entity's Board of Directors or advisory committees.