A PHASE-I CLINICAL AND PHARMACOKINETIC STUDY OF THE NEW TOPOISOMERASEINHIBITOR GI147211 GIVEN AS A 72-H CONTINUOUS-INFUSION

GI147211 is a navel, totally synthetic camptothecin with promising pre clinical and early clinical activity. This study was designed to deter mine the maximum tolerated dose of GI147211 as a 72-h infusion and to describe its pharmacokinetics and pharmacodynamics on this schedule. I n a single-arm, rising-dose study in patients with advanced cancer, ei ght cohorts of three or more patients received 72-h infusions of GI147 211 at doses ranging from 0.25 to 2.5 mg m(-2) day(-1). Forty-four pat ients received a total of 124 cycles. All patients had refractory tumo urs and 40 had received prior chemotherapy and/or radiotherapy. Whole- blood GI147211 lactone, total blood and total concentrations were meas ured during and over the 12 h following the infusion. Myelosuppression was observed at all dose levels. Neutropenia was dose limiting at 2.0 mg m(-2) day(-1) in minimally pretreated patients, while both neutrop enia and thrombocytopenia were limiting at 1.5 mg m(-2) day(-1) in tho se more heavily pretreated. Phlebitis occurred with infusions through peripheral veins early in this study, necessitating the use of central Venous access. Other toxicities included mild nausea and vomiting, fa tigue, headache, central venous catheter infections and alopecia. Thre e partial and two minor responses lasting 8-34+ weeks were noted in pa tients with ovarian, colon and breast carcinomas and hepatoma. Mean st eady-state concentrations of GI147211 increased with dose over a range of 0.25-1.24 ng ml(-1). The mean terminal elimination half-life was 7 .5 h, and the clearance averaged 1074 mi min(-1) m(-2) over the doses studied. The mean fractional excretion of unchanged drug in urine was 0.114. GI147211 lactone exposure correlated with haematological toxici ty. The recommended phase II doses for this regimen are 1.75 mg m-2 da y(-1) and 1.2 mg m(-2) day(-1) for minimally pretreated and heavily pr etreated patients respectively. At these doses, steady-state GI147211 concentrations within the range of those effective in vitro were achie ved. Extensive phase II evaluation of this compound and further phase I trials evaluating more prolonged infusions are ongoing.