INTRODUCTION: Bortezomib is a small-molecule proteasome inhibitor with single-agent activity in patients with non-small cell lung carcinoma (NSCLC) and synergy with gemcitabine in preclinical studies. The combination of gemcitabine and carboplatin is an accepted first-line treatment for advanced NSCLC. We conducted a phase I study of gemcitabine and carboplatin in combination with bortezomib. METHODS: Bortezomib was administered on days 1, 4, 8, and 11, after gemcitabine on days 1 and 8, and carboplatin on day 1 of a 21-day cycle. Three escalating dose levels were evaluated: bortezomib 1.0 mg/m/gemcitabine 800 mg/m, bortezomib 1.0 mg/m/gemcitabine 1000 mg/m, and bortezomib 1.3 mg/m/gemcitabine 1000 mg/m, in combination with carboplatin AUC 5.0. RESULTS: Twenty-six patients with advanced NSCLC were treated; 21 were chemotherapy-naive. The median age was 59 years (range, 34-74), and 23 patients were stage IV. The Karnofsky performance score was ≤80% in 10 and >80% in 16 patients. Dose-limiting toxicities were grade 3 thrombocytopenia with bleeding and febrile neutropenia accompanied by grade 4 thrombocytopenia and grade 3 hyponatremia. The maximum-tolerated dose was defined as bortezomib 1.0 mg/m, gemcitabine 1000 mg/m, and carboplatin AUC 5.0. The most common grade 3/4 toxicities were thrombocytopenia (rarely associated with bleeding), and neutropenia. Nine of 26 patients (35%) achieved partial response, and eight patients had stable disease. CONCLUSIONS: The combination of bortezomib 1.0 mg/m, gemcitabine 1000 mg/m, and carboplatin AUC 5.0 demonstrated manageable toxicities and encouraging activity in NSCLC. This regimen was used in a phase II study.
- Non-small cell lung cancer
- Proteasome inhibitor
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine