A phase I study of bi-weekly administration of 24-h gemcitabine followed by 24-h irinotecan in patients with solid tumors.

OBJECTIVE

To determine the maximal tolerated doses (MTD) and dose-limiting toxicities (DLT) of combination of 24-h infusions of gemcitabine and irinotecan in patients with advanced solid tumors.

METHODS

Twenty-four patients with advanced solid tumors received gemcitabine as a 24-h IV infusion followed by a 24-h infusion of irinotecan every 2 weeks. Pharmacokinetic parameters of both drugs and their metabolites were estimated by using non-compartmental methods.

RESULTS

Twenty-four patients were fully evaluable for toxicity. DLT was observed in two of six patients at irinotecan/gemcitabine 110/150 mg/m(2) (grade 3 diarrhea and grade 3 GI bleeding). No patient developed acute cholinergic symptoms at any dose. Other toxicities were < or =grade 2 nausea, vomiting, and fatigue. Tumor responses were observed in three patients (one CR: cholangiocarcinoma; two PR: SCLC, gastric neuroendocrine tumor). Stable disease >3 months was found in six patients including five patients who had failed short infusions of either drug. Pharmacokinetic analysis showed that C (max) of each drug and active metabolites were dose-dependent. High dose of gemcitabine increased C (max), AUC, and T(1/2) of irinotecan. However, gemcitabine had minimal effects on SN-38.

CONCLUSIONS

The recommended dose for Phase II studies is gemcitabine 125 mg/m(2) given as a 24-h IV infusion on D1 and D15, followed by a 24-h IV infusion of irinotecan 110 mg/m(2) on D2 and D16. Both pretreated patients and chemo-naive patients seem to tolerate higher doses of this combination without significant toxicities. Objective responses among patients with solid tumors, in particular cholangiocarcinoma and small cell lung cancer merits further investigation.