The proteasome inhibitor bortezomib in combination with gemcitabine and carboplatin in advanced non-small cell lung cancer: A California Cancer Consortium phase I study

Angela M. Davies, Christopher Ruel, Primo N Lara, Derick H Lau, Paul H. Gumerlock, Richard J Bold, Stephen Shibata, Heinz Josef Lenz, David P. Schenkein, David R Gandara

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)68-74
Number of pages7
JournalJournal of Thoracic Oncology
Volume3
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Bortezomib
  • Carboplatin
  • Gemcitabine
  • Non-small cell lung cancer
  • Proteasome inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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