A parallel dose-escalation study of weekly and twice-weekly bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced solid tumors.

PURPOSE

To establish maximum tolerated dose (MTD) and tolerability of two schedules of bortezomib in combination with cisplatin and gemcitabine as first-line treatment of patients with advanced solid tumors.

EXPERIMENTAL DESIGN

Patients were assigned to increasing doses of bortezomib days 1 and 8 (weekly schedule) or days 1, 4, 8, and 11 (twice-weekly schedule), in addition to gemcitabine 1,000 mg/m(2) days 1 and 8 and cisplatin 70 mg/m(2) day 1, every 21 days. Maximum of six cycles. Plasma pharmacokinetics of cisplatin and gemcitabine were determined at MTD.

RESULTS

Thirty-four patients were enrolled of whom 27 had non-small cell lung cancer (NSCLC). Diarrhea, neutropenia, and thrombocytopenia were dose-limiting toxicities leading to an MTD of bortezomib 1.0 mg/m(2) in the weekly schedule. Febrile neutropenia and thrombocytopenia with bleeding were dose-limiting toxicities in the twice-weekly schedule, leading to an MTD of bortezomib 1.0 mg/m(2) as well. Most common > or =grade 3 treatment-related toxicities were thrombocytopenia and neutropenia. No grade > or =3 treatment-related sensory neuropathy was reported. Of 34 evaluable patients, 13 achieved partial responses, 17 stable disease, and 4 progressive disease. Response and survival of NSCLC patients treated with twice weekly or weekly bortezomib were similar. However, increased dose intensity of bortezomib led to increased gastrointestinal toxicity as well as myelosuppression. Pharmacokinetic profiles of cisplatin and gemcitabine were not significantly different in patients receiving either schedule.

CONCLUSIONS

Weekly bortezomib 1.0 mg/m(2) plus gemcitabine 1,000 mg/m(2) and cisplatin 70 mg/m(2) is the recommended phase 2 schedule, constituting a safe combination, with activity in NSCLC.