Journal of Clinical Oncology, Vol 16, 3302-3309, Copyright © 1998 by American Society of Clinical Oncology
Phase I and pharmacologic study of continuous infusion topotecan in combination with cisplatin in patients with advanced cancer: a Cancer and LeukemiaGroup B study
RC Lilenbaum, AA Miller, G Batist, S Bernard, DR Hollis, GL Rosner, MJ Egorin, RL Schilsky and MJ Ratain
Mt. Sinai Comprehensive Cancer Center, Miami Beach, FL 33140, USA. rlilenba@mtsccc.salick.com
PURPOSE: Preclinical and clinical data suggest that topotecan may be more
effective, and perhaps less toxic, when administered as a continuous
intravenous infusion (CIVI). A previous Cancer and Leukemia Group B (CALGB)
trial of topotecan, given on a daily bolus schedule in combination with
cisplatin, produced more hematologic toxicity than expected with either
drug alone. Therefore, we designed this phase I trial to define the
dose-limiting toxicities (DLTs) and the recommended phase II doses of
cisplatin in combination with topotecan administered as a CIVI. Population
pharmacodynamic models for the combination also were investigated. PATIENTS
AND METHODS: Patients with advanced solid tumors and a maximum of one prior
chemotherapy regimen for metastatic disease were eligible if they had a
performance status of 0 to 1 and adequate renal, hepatic, and bone marrow
function. Prior treatment with camptothecins or platinum compounds and
prior pelvic irradiation were not allowed. The initial schedule consisted
of a fixed dose of topotecan 0.4 mg/m2/d administered as a CIVI for 21 days
and escalating doses of cisplatin administered on days 1, 8, and 15 of a
28-day schedule, until the maximum tolerated dose (MTD) was achieved. After
severe hematologic toxicity was observed in the first two patients, the
topotecan infusion was shortened to 14 days, and the total dose of
cisplatin was administered on day 1 in all subsequent patients. After the
MTD was defined, that cohort was expanded to include a total of 12
assessable patients. Hematopoietic growth factors were not allowed. For the
pharmacologic studies, total topotecan plasma concentrations were measured
by high-pressure liquid chromatography (HPLC) during infusion on days 3, 8,
and 11 on the first cycle, and the median steady-state concentration (Tss)
was determined. Platinum plasma concentrations on day 3 were measured by
atomic absorption spectrometry. RESULTS: Of the 32 patients enrolled, 28
were assessable for toxicity and 24 for response. The primary toxicity was
hematologic, with both neutropenia and thrombocytopenia being
dose-limiting. The MTD of cisplatin was 75 mg/m2 on day 1 in combination
with topotecan 0.4 mg/m2/d for 14 days. At this dose level, three of a
total of 12 assessable patients had DLT. The pharmacodynamic relationship
between Tss and the absolute neutrophil count at the nadir (ANCn) was
described by the following equation: log10 (ANCn)=4.23 - 0.47 x Tss - 0.01
x cisplatin dose (P < .0001; R2=0.64). The substitution of platinum
concentration for cisplatin dose in this model did not result in a
significant improvement. Three patients had a partial response: one with
duodenal carcinoma; a second with small-cell lung cancer; and a third with
melanoma. CONCLUSION: Cisplatin can be given safely in combination with
CIVI topotecan. However, toxicity was still substantial. Based on the
current results and our previous trial of this combination, we conclude
that, when combined with cisplatin, CIVI topotecan does not seem to be
advantageous compared with the more traditional daily bolus schedule.
