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Clinical Trials |
Divisions of Medical Oncology [H. C. P., R. M. G., C. E., J. R., P. A. B., A. A. A., S. A. A.] and Oncology Research [J. M. R.] and Section of Biostatistics [J. A. S., P. A. S.], Mayo Clinic, Rochester, Minnesota 55905 and Pharmacia & Upjohn Company, Peapack, New Jersey 07977 [L. J. S., G. E., L. L. M.]
A
Phase I study was performed to determine the maximum tolerated dose
(MTD), toxicities, and pharmacokinetic profile of irinotecan (CPT-11)
and its active metabolites when given on a once-every-3-week schedule.
Thirty-four patients with advanced refractory solid malignancies were
treated with CPT-11 (240–340 mg/m2) administered as a
90-min i.v. infusion every 3 weeks. Patients were divided into two
groups: those with and those without prior abdominal/pelvic (AP)
radiotherapy. Gastrointestinal toxicity (nausea, vomiting, and
diarrhea) and hematological toxicity (leukopenia and neutropenia) were
dose-limiting side effects. Other common toxicities included anorexia,
asthenia, and acute cholinergic symptoms (abdominal cramps,
diaphoresis, and lacrimation). For patients with no prior AP radiation
therapy, the MTD was determined to be 320 mg/m2, whereas
those with prior AP radiation therapy had a MTD of 290
mg/m2. Dose-proportional increases in the mean area under
the concentration-time curves for CPT-11, SN-38, and SN-38G were not
observed over the narrow dose range studied. Mean values of terminal
phase half-life, clearance, terminal phase volume of
distribution, and steady-state volume of distribution for CPT-11
were 12.4 ± 1.8 h, 13.0 ± 3.8 liters/h/m2,
234 ± 83 liters/m2, and 123 ± 38
liters/m2, respectively. The pharmacodynamic analyses
indicated the strongest correlation to be between SN-38 area under the
concentration-time curves and neutropenia (
= 0.60;
P = 0.001). A total of five responses (one complete
response and four partial responses) were observed in the cohort of 32
patients with previously treated metastatic colorectal carcinoma. In
conclusion, gastrointestinal toxicity and hematological toxicity were
the dose-limiting toxicities of CPT-11 when administered as a
90-min infusion every 3 weeks. In this trial, the recommended Phase
II starting dose for patients with no prior AP radiation therapy was
found to be 320 mg/m2; for patients with prior AP
radiation, the recommended Phase II starting dose was 290
mg/m2. This once-every-3-week schedule has been
incorporated into a Phase I trial of CPT-11 combined with
5-fluorouracil and leucovorin.
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