Phase I trial of dose-escalated paclitaxel and carboplatin in combination with ifosfamide and filgrastim: preliminary results.

The purpose of this phase I study is to determine the maximally tolerated doses of paclitaxel and carboplatin (dosed by area under the concentration-time curve) when given at specified times in combination with 6 g/m2 ifosfamide (3 g/m2 at 8 AM on days 1 and 2) with mesna and 5 microg/kg/d filgrastim (from day 4 until the absolute neutrophil count is > 10,000/microL) every 21 days for six cycles. Twelve patients have been treated thus far, 10 of whom are currently eligible for toxicity and response analyses: three each at dose levels 1 and 2, and four at dose level 3. Hematologic toxicity has been the only grade 4 toxicity noted. Only one episode of neutropenic fever occurred in the 43 cycles delivered to date, and only one patient experienced an ifosfamide-related change in mental status. Two patients have developed reversible renal tubular acidosis. No other significant neurologic or renal toxicities have been noted. Patient disease distribution is three non-small cell lung cancer, two breast cancer, two adenocarcinomas of unknown primary site, one prostate cancer, one angioimmunoblastic lymphadenopathy, and one mesothelioma. The median age is 48 years (age range, 34 to 75 years), and median prior chemotherapy treatments was zero. One patient on dose level 1 required a dose delay on cycle 6 because of inadequate hematologic recoveries and one patient required a 50% reduction of the ifosfamide dose during cycle 4 due to mental status change. No patients receiving dose level 2 required dose reductions or delays. One patient at dose level 2 was removed from study due to deterioration of performance status and subsequently died. At dose level 3 dose delays have been required in six of 15 cycles, but no dose reductions have been necessary. Four patients have achieved a complete response (40%) and six a partial response (60%), for a total response rate of 100%. At the completed dose levels, this regimen appears to be tolerable and active with minimal nonhematologic toxicities.