Assessment of maximum tolerated dose (MTD) of FK463 in cancer patients undergoing HSCT

R Powles, R Chopra, HG Prentice, N Russel, B Sirohi.


In an earlier U.S. study the MTD was not reached in FK463 doses up to 200mg/day. This study was designed to look at doses above 200mg/day. Sequential groups of 10 patients received 3.0 and 4.0 mg/kg/day one-hour i.v. FK463, respectively, with two further dosage groups planned (6.0 and 8.0 mg/kg/day).The treatment period was 7-28 days; treatment was stopped upon recovery of neutropenia or initiation of empirical antifungal therapy. Adverse events were graded according to the Southwest Oncology Group Toxicity Criteria. The IMITID 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. Patients in the 3.0 and 4.0 mg/kg/day dosage groups were treated for a median of 16.5 and 18.5 days, respectively at mean doses of 233rng/day (range, 175-275mg) and 289mg/day (range, 175-375mg).Adverse events tended to be disease-related. In the 3 mg/kg group, Grade 1 and 2 toxicities assessed as causally related comprised 1 patient with vomiting, cellulitis, diarrhea, fever and somnolence, 1 with general edema, fever, nausea, albuminuria, and 1 with hypocalcemia. In the 4.0 mg/kg/day group, Grade 2 phlebitis was reported for 2 patients, and Grade 1 dyspepsia for 1 patient. There was no Grade 3 or Grade 4 adverse event that was assessed by the investigator as treatment- related. Empirical antifungal therapy was started for 3 patients in each group. In conclusion, FK463 was well tolerated and the MTID was not reached.

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Trends in Invasive fungal Infections 6, 2001
    • TIFI 6th