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

被引:30
作者
Davies, Angela M. [1 ]
Ruel, Christopher [1 ,2 ]
Lara, Primo N. [1 ]
Lau, Derick H. [1 ]
Gumerlock, Paul H. [1 ]
Bold, Richard
Shibata, Stephen [2 ,3 ]
Lenz, Heinz-Josef
Schenkein, David P. [4 ]
Gandara, Anddavid R.
机构
[1] Calif State Univ Sacramento, Div Hematol & Oncol, Davis Canc Ctr, Sacramento, CA 95819 USA
[2] Hope Natl Med Ctr, Div Med Oncol, Duarte, CA USA
[3] Univ So Calif, Div Med Oncol, Los Angeles, CA USA
[4] Millennium Pharmaceut Inc, Cambridge, MA USA
关键词
bortezomib; carboplatin; gemcitabine; non-small cell lung cancer; proteasome inhibitor;
D O I
10.1097/JTO.0b013e31815e8b88
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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(2)/gemcitabine 800 mg/m(2), bortezomib 1.0 mg/m(2)/gemcitabine 1000 mg/m(2), and bortezomib 1.3 mg/m(2)/gemcitabine 1000 mg/m(2), 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(2), gemcitabine 1000 mg/m(2), 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(2), gemcitabine 1000 mg/m(2), and carboplatin AUC 5.0 demonstrated manageable toxicities and encouraging activity in NSCLC. This regimen was used in a phase II study.
引用
收藏
页码:68 / 74
页数:7
相关论文
共 50 条
  • [41] Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors
    Ryan, David P.
    Appleman, Leonard J.
    Lynch, Thomas
    Supko, Jeffrey G.
    Fidias, Panagiotis
    Clark, Jeffrey W.
    Fishman, Mayer
    Zhu, Andrew X.
    Enzinger, Peter C.
    Kashala, Oscar
    Cusack, James, Jr.
    Eder, Joseph P.
    [J]. CANCER, 2006, 107 (10) : 2482 - 2489
  • [42] Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer
    Sandler, Alan
    Gray, Robert
    Perry, Michael C.
    Brahmer, Julie
    Schiller, Joan H.
    Dowlati, Afshin
    Lilenbaum, Rogerio
    Johnson, David H.
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2006, 355 (24) : 2542 - 2550
  • [43] Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer
    Schiller, JH
    Harrington, D
    Belani, CP
    Langer, C
    Sandler, A
    Krook, J
    Zhu, JM
    Johnson, DH
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2002, 346 (02) : 92 - 98
  • [44] Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs
    Screnci, D
    McKeage, MJ
    Galettis, P
    Hambley, TW
    Palmer, BD
    Baguley, BC
    [J]. BRITISH JOURNAL OF CANCER, 2000, 82 (04) : 966 - 972
  • [45] Stevenson JP, 2004, J CLIN ONCOL, V22, p652S
  • [46] Therasse P, 2000, J NATL CANCER I, V92, P205, DOI 10.1093/jnci/92.3.205
  • [47] Cell cycle disturbances and apoptosis induced by topotecan and gemcitabine on human lung cancer cell lines
    Tolis, C
    Peters, GJ
    Ferreira, CG
    Pinedo, HM
    Giaccone, G
    [J]. EUROPEAN JOURNAL OF CANCER, 1999, 35 (05) : 796 - 807
  • [48] 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
    Voortman, Jens
    Smit, Egbert F.
    Honeywell, Richard
    Kuenen, Bart C.
    Peters, Godefridus J.
    de Velde, Helgi van
    Giaccone, Giuseppe
    [J]. CLINICAL CANCER RESEARCH, 2007, 13 (12) : 3642 - 3651
  • [49] Proteasome inhibitor PS-341, induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c-Jun/AP-1 signaling
    Yang, Y
    Ikezoe, T
    Saito, T
    Kobayashi, M
    Koeffler, HP
    Taguchi, H
    [J]. CANCER SCIENCE, 2004, 95 (02): : 176 - 180
  • [50] Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer:: a phase III randomized trial
    Zatloukal, P
    Petruzelka, L
    Zemanová, M
    Kolek, V
    Skricková, J
    Pesek, M
    Fojtu, H
    Grygárková, I
    Sixtová, D
    Roubec, J
    Horenková, E
    Havel, L
    Prusa, P
    Nováková, L
    Skácel, T
    Kuta, M
    [J]. LUNG CANCER, 2003, 41 (03) : 321 - 331