Background: In an earlier U.S. study, the MTD was not reached in FK463 doses up to 200 mg/day. This study was designed to look at doses above 200mg/day. Methods: Sequential groups of 10 patients received 3.0 and 4.0 mg/kg/day FK463, respectively, with two further dosage groups planned (6.0 and 8.0 mg/kg/day). Treatment (by infusion) was for a minimum of 7 days and a maximum of 28 days. After 7 days, treatment was stopped following the recovery of neutropenia (>0.5 x 109/L), or the need to initiate empirical antifungal therapy. Adverse events were graded, from 1 to 4 (least to most severe) according to the Southwest Oncology Group Toxicity Criteria. The MTD was defined as the highest dose of FK463 that did not cause the same treatment-related Grade 3 or 4 adverse event in at least 3 patients. Results: The median treatment period was 16.5 (range 13 to 28 days) and 18.5 (8 to 28 days) for all patients who received 3.0 and 4.0 mg/kg/day FK463, respectively. Empirical antifungal therapy was started for 3 patients in each dosage group. The mean dose was 233mg/day, (range, 175-275mg) and 289mg/day (range, 175-375mg) for the 3.0 and 4.0 mg/kg/day dosing groups, respectively. Adverse events tended to be disease-related. In the 3 mg/kg/day group, Grade 1 and 2 toxicities assessed as causally related comprised one patient with vomiting, cellulitis, diarrhea, fever and somnolence, one with general edema, fever, nausea, albuminuria, and one with hypocalcemia. In the 4.0 mg group, two patients with Grade 2 phlebitis, and one patient with Grade 1 dyspepsia. There was no Grade 3 or Grade 4 adverse event that was assessed by the investigator as treatment-related. Conclusion: FK463 was well tolerated. After completion of the first two dosage groups (3 and 4 mg/kg/day), the MTD was not reached.
Full conference title:
- ICAAC 41st