Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors

Bortezomib is the first proteasome inhibitor to show preliminary evidence of activity against solid tumors. Findings from preclinical studies prompted a Phase I trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of bortezomib in combination with gemcitabine in patients with recurring/refractory advanced solid tumors. The effect of gemcitabine on proteasome inhibition by bortezomib in whole blood was also investigated.

Bortezomib was administered as an intravenous bolus injection on Days 1, 4, 8, and 11, with gemcitabine (30-minute infusion) on Days 1 and 8 of a 21-day cycle. Groups of > or =3 patients were evaluated at each dose level. Escalating doses of gemcitabine 500 mg/m(2) to 1000 mg/m(2) with bortezomib 1.0 mg/m(2) to 1.5 mg/m(2) were planned.

There were no DLTs in patients receiving bortezomib 1.0 mg/m(2) and gemcitabine 500 mg/m(2) to 1000 mg/m(2) in the first 3 dose levels. Dose-limiting nausea, vomiting, gastrointestinal obstruction, and thrombocytopenia occurred in 4 of 5 evaluable patients in dose level 4 (bortezomib 1.3 mg/m(2), gemcitabine 800 mg/m(2)), establishing bortezomib 1.0 mg/m(2) and gemcitabine 1000 mg/m(2) as the MTD. Most common Grade > or =3 toxicities were neutropenia (6 patients), thrombocytopenia (5 patients), gastrointestinal disorders (6 patients), and general disorders (4 patients) such as fatigue. One patient with nonsmall cell lung carcinoma achieved a partial response and 7 achieved stable disease. Inhibition of 20S proteasome activity by bortezomib was unaffected by gemcitabine coadministration.

Dosages of bortezomib and gemcitabine suitable for further evaluation of antitumor activity have been established.