Phase I study of 3-week schedule of irinotecan combined with cisplatin in patients with advanced solid tumors.

PURPOSE: To assess the feasibility, pharmacokinetic interaction, and possible sequence-dependent effects of the irinotecan/cisplatin combination given every 3 weeks, and to assess the influence of additional granulocyte colony-stimulating factor (G-CSF) on the hematologic toxicity. PATIENTS AND METHODS: Patients who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of a 90-minute irinotecan infusion followed by a 3-hour cisplatin infusion on day 1, with cycles repeated once every 3 weeks. After the maximum-tolerated dose was determined, the sequence of administration was reversed. In a separate cohort of six patients, we assessed the effect of G-CSF on the experienced hematologic toxicity and dose-intensity. Irinotecan doses ranged from 175 to 300 mg/m(2) and cisplatin doses ranged from 60 to 80 mg/m(2). RESULTS: Fifty-two patients entered the study; one was not eligible, and two were not assessable for response. Twenty-five patients were pretreated, and 26 were not. Fifty-one patients received a total of 223 courses. The dose-limiting toxicity was a combination of neutropenic fever, diarrhea, and fatigue at a dose level combining irinotecan 300 mg/m(2) with cisplatin 80 mg/m(2). Neutropenia was common (grades 3 to 4, 68%). Irinotecan pharmacokinetics were linear over the dose range studied. No sequence-dependent side effects were observed. Tumor responses included three complete responses and eight partial responses. CONCLUSION: For phase II studies, we recommend irinotecan 260 mg/m(2) combined with cisplatin 80 mg/m(2) once every 3 weeks for chemotherapy-naive patients in good physical condition, and irinotecan 200 mg/m(2) combined with cisplatin 80 mg/m(2) for other patients.

Pharmacokinetic, metabolic, and pharmacodynamic profiles in a dose-escalating study of irinotecan and cisplatin.

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of irinotecan and cisplatin administered once every 3 weeks in a dose-escalating study in patients with solid tumors. PATIENTS AND METHODS: Fifty-two cancer patients were treated with irinotecan administered as a 90-minute infusion at doses ranging from 175 to 300 mg/m(2) followed by cisplatin administered as a 3-hour intravenous infusion at doses ranging from 60 to 80 mg/m(2). After reaching the maximum-tolerated dose, the sequence of drug administration was revised. For pharmacokinetic analysis, serial plasma samples were obtained on days 1 through 3 of the first cycle. Forty-five patients were assessable for irinotecan pharmacokinetics, and 46 were assessable for cisplatin pharmacokinetics. RESULTS: Irinotecan and cisplatin demonstrated linear pharmacokinetics comparable to that observed with single-agent administration, which suggests an absence of pharmacokinetic interaction. SN-38G constituted the major plasma metabolite of irinotecan, whereas 7-ethyl-10-[4-N-(1-piperidino)1-amino]-carbonyloxycamptothecine (NPC) was only a minor metabolite in plasma, possibly indicating a rapid conversion of NPC to SN-38. The terminal elimination phases of SN-38 and SN-38G were similar and relatively delayed when compared with the elimination of irinotecan. Maximal DNA adduct formation did not significantly differ from that observed with single-agent administration. The percentage decrease in WBC was significantly related to the areas under the plasma concentration-time curve (AUCs) of the lactone form of irinotecan (P =.0245) and SN-38 (P =. 0123). The severity of diarrhea was not significantly related to the AUCs of irinotecan and SN-38, nor to the systemic glucuronidation rate of SN-38. CONCLUSION: There was no apparent pharmacokinetic interaction between irinotecan and cisplatin in this study. Reversion of the administration sequence of the drugs did not seem to have any influence on the pharmacokinetics. The incidence and severity of delayed-type diarrhea was not related to any of the studied parameters.

Drug-administration sequence does not change pharmacodynamics and kinetics of irinotecan and cisplatin.

In this study, 11 patients with solid tumors were randomized to receive irinotecan (CPT-11; 200 mg/m2) as a 90-min i.v. infusion, immediately followed by cisplatin (CDDP; 80 mg/m2) as a 3-h i.v. infusion in the first course and the reversed sequence in the second course or vice versa. No significant differences in any toxicity were observed between the treatment schedules (decrease in absolute neutrophil count, 74.7 +/- 18.3 versus 80.3 +/- 18.0%; P = 0.41). CPT-11 lactone clearance was similar to single agent data and not significantly different between study courses (60.4 +/- 17.1 versus 65.5 +/- 16.3 liter/h/m2; P = 0.66). The kinetic profiles of the major CPT-11 metabolites SN-38, SN-38 glucuronide, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidinolcarbonyloxycamptothecine (APC), and 7-ethyl-10-[4-N-(1-piperidino)-1-amino]carbonyloxycamptothecine (NPC) were also sequence independent (P > or = 0.20). In addition, CPT-11 had no influence on the clearance of nonprotein-bound CDDP (40.8 +/- 16.7 versus 50.3 +/- 18.6 liter/h/m2; P = 0.08) and the platinum DNA-adduct formation in peripheral leukocytes in either sequence (1.94 +/- 2.20 versus 2.42 +/- 1.62 pg Pt/microg DNA; P = 0.41). These data indicate that the toxicity of the combination CPT-11 and CDDP is schedule independent and that there is no mutual pharmacokinetic interaction.

Phase I and pharmacologic study of the arotinoid Ro 40-8757 in combination with cisplatin and etoposide in patients with non-small cell lung cancer.

This phase I study was performed to assess the feasibility of combining cisplatin/etoposide (VP-16) with the arotinoid Ro 40-8757 and to determine the dose-limiting toxicity (DLT) of Ro 40-8757 in this combination. Patients with non-small cell lung cancer were eligible. Treatment consisted of Ro 40-8757 p.o. day 1-21, cisplatin 100 mg/m2 i.v. on day 2 and VP-16 100 mg/m2 i.v. on day 2-4, repeated every 3 weeks. Eighteen patients were evaluable for toxicity and response. The doses of Ro 40-8757 ranged from 84 mg/m2 once daily to 42 mg/m2 thrice daily (tid). DLT consisting of delayed nausea/vomiting was reached at 42 mg/m2 tid. Consequently, the maximum tolerated dose was set at one dose level below the DLT, i.e. 28 mg/m2 tid. Skin toxicity occurred but was well manageable. Pharmacological analyses showed a small increase in the volume of distribution of cisplatin and VP-16 between the first and third course. However, no relationship with side effects was found. A response was achieved in 50% of patients. The combination of cisplatin/VP-16 with Ro 40-8757 appears to be feasible at a dose schedule of 28 mg/m2 tid. The response rate was at the upper rate of what can be expected with cisplatin and VP-16.