Phase II clinical trial evaluating docetaxel, vinorelbine and GM-CSF in stage IV melanoma

Zeynep Eroglu, Kevin M Kong, James G Jakowatz, Wolfram Samlowski, John P Fruehauf, Zeynep Eroglu, Kevin M Kong, James G Jakowatz, Wolfram Samlowski, John P Fruehauf

Abstract

Purpose: Metastatic melanoma patients have a poor prognosis. No chemotherapy regimen has improved overall survival. More effective treatments are needed. Docetaxel has clinical activity in melanoma and may be more active when combined with vinorelbine. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown activity as an adjuvant melanoma therapy. We carried out a phase II study of these agents in patients with stage IV melanoma.

Methods: Patients had documented stage IV melanoma and may have had prior immuno or chemotherapy. Previously treated brain metastases were allowed. Docetaxel (40 mg/m(2) IV) and vinorelbine (30 mg/m(2) IV) were administered every 14 days, followed by GM-CSF (250 mg/m2 SC on days 2 to 12). The primary endpoint of the study was 1-year overall survival (OS). Secondary objectives were median overall survival, response rate (per RECIST criteria), and the toxicity profiles.

Results: Fifty-two patients were enrolled; 80% had stage M1c disease. Brain metastases were present in 21%. Fifty-two percent of patients had received prior chemotherapy, including 35% who received prior biochemotherapy. Toxicity was manageable. Grade III/IV toxicities included neutropenia (31%), anemia (14%), febrile neutropenia (11.5%), and thrombocytopenia (9%). DVS chemotherapy demonstrated clinical activity, with a partial response in 15%, and disease stabilization in 37%. Six-month PFS was 37%. Median OS was 11.4 months and 1-year OS rate was 48.1%.

Conclusions: The DVS regimen was active in patients with advanced, previously treated melanoma, with manageable toxicity. The favorable 1-year overall survival and median survival rates suggest that further evaluation of the DVS regimen is warranted.

Figures

Fig. 1
Fig. 1
Kaplan–Meier plot of progression-free survival (n = 52, 7 cases censored; median PFS = 134 days)
Fig. 2
Fig. 2
Kaplan–Meier plot of median overall survival (n = 52, 11 cases censored; median OS = 320 days)

References

    1. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. Cancer J Clin 59:225–249
    1. Markovich S, Erickson L, Rao R. Malignant melanoma in the 21st century, Part 2: staging, prognosis, and treatment. Mayo Clin Proc. 2007;82:490–513. doi: 10.4065/82.4.490.
    1. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18:158–166.
    1. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105–2116.
    1. Smith FO, Downey SG, Klapper JA, Yang JC, Sherry RM, Royal RE, Kammula US, Hughes MS, Restifo NP, Levy CL, White DE, Steinberg SM, Rosenberg SA. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008;14:5610–5618. doi: 10.1158/1078-0432.CCR-08-0116.
    1. Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the eastern cooperative oncology group. J Clin Oncol. 2008;2:5748–5754. doi: 10.1200/JCO.2008.17.5448.
    1. Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002;20:2045–2052. doi: 10.1200/JCO.2002.07.044.
    1. Ives NJ, Stowe RL, Lorigan P, Wheatley K. Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2, 621 patients. J Clin Oncol. 2007;25:5426–5434. doi: 10.1200/JCO.2007.12.0253.
    1. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723. doi: 10.1056/NEJMoa1003466.
    1. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–819. doi: 10.1056/NEJMoa1002011.
    1. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–977. doi: 10.1038/nature09626.
    1. Photiou A, Shah P, Leong LK, Moss J, Retsas S. In vitro synergy of paclitaxel (Taxol) and vinorelbine (Navelbine) against human melanoma cell lines. Eur J Cancer. 1997;33:463–470. doi: 10.1016/S0959-8049(97)89023-5.
    1. Neale MH, Myatt NE, Khoury GG, Weaver P, Lamont A, Hungerford JL, Kurbacher CM, Hall P, Corrie PG, Cree IA. Comparison of the ex vivo chemosensitivity of uveal and cutaneous melanoma. Melanoma Res. 2001;11:601–609. doi: 10.1097/00008390-200112000-00006.
    1. Wu H, Xin Y, Zhao J, Sun D, Li W, Hu Y, Wang S (2011) Metronomic docetaxel chemotherapy inhibits angiogenesis and tumor growth in a gastric cancer model. Cancer Chemother Pharmacol Feb 3. [Epub ahead of print]
    1. Sanchez JM, Balana C, Font A, Sánchez JJ, Manzano JL, Guillot M, Margelí M, Richardet M, Rosell R. Phase II non-randomized study of three different sequences of docetaxel and vinorelbine in patients with advanced non-small cell lung cancer. Lung Cancer. 2002;38:309–315. doi: 10.1016/S0169-5002(02)00220-9.
    1. Rodriguez J, Calvo E, Cortes J, Santisteban M, Perez-Calvo J, Martínez-Monge R, Brugarolas A, Fernandez-Hidalgo O. Docetaxel plus vinorelbine as salvage chemotherapy in advanced breast cancer: a phase II study. Breast Cancer Res Treat. 2002;76:47–56. doi: 10.1023/A:1020273502426.
    1. Gomez-Bernal A, Cruz JJ, Garcia-Palomo A, Arizcun A, Pujol E, Diz P, Martín G, Fonseca E, Sánchez P, Rodríguez C, del Barco E, López Y. Biweekly docetaxel and vinorelbine in anthracycline-resistant metastatic breast cancer: a multicenter phase II study. Am J Clin Oncol. 2003;26:127–131. doi: 10.1097/00000421-200304000-00005.
    1. Retsas S, Mohith A, Mackenzie H. Taxol and vinorelbine: a new active combination for disseminated malignant melanoma. Anticancer Drugs. 1996;7:161–165. doi: 10.1097/00001813-199602000-00003.
    1. Jimeno A, Hitt R, Quintela-Fandino M. Phase II trial of vinorelbine tartrate in patients with treatment-naive metastatic melanoma. Anticancer Drugs. 2005;16:53–57. doi: 10.1097/00001813-200501000-00007.
    1. Whitehead RP, Moon J, McCachren SS, Hersh EM, Samlowski WE, Beck JT, Tchekmedyian NS, Sondak VK. A Phase II trial of vinorelbine tartrate in patients with disseminated malignant melanoma and one prior systemic therapy: a southwest oncology group study. Cancer. 2004;100:1699–1704. doi: 10.1002/cncr.20183.
    1. Feun LG, Savaraj N, Hurley J, Marini A, Lai S. A clinical trial of intravenous vinorelbine tartrate plus tamoxifen in the treatment of patients with advanced malignant melanoma. Cancer. 2000;88:584–588. doi: 10.1002/(SICI)1097-0142(20000201)88:3<584::AID-CNCR14>;2-#.
    1. Fidler IJ, Kleinerman ES. Lymphokineactivated human blood monocytes destroy tumor cells but not normal cells under cocultivation conditions. J Clin Oncol. 1984;2:937–943.
    1. Grabstein KH, Urdal DL, Tushinski RJ, Mochizuki DY, Price VL, Cantrell MA, Gillis S, Conlon PJ. Induction of macrophage tumoricidal activity by granulocyte-macrophage colonystimulating factor. Science. 1986;232:506–508. doi: 10.1126/science.3083507.
    1. Thomassen MJ, Barna BP, Rankin D, Wiedemann HP, Ahmad M. Differential effect of recombinant granulocyte macrophage colony-stimulating factor on human monocytes and alveolar macrophages. Cancer Res. 1989;49:4086–4089.
    1. Wing EJ, Magee DM, Whiteside TL, Kaplan SS, Shadduck RK. Recombinant human granulocyte/macrophage colony-stimulating factor enhances monocyte cytotoxicity and secretion of tumor necrosis factor alpha and interferon in cancer patients. Blood. 1989;73:643–646.
    1. Chachoua A, Oratz R, Hoogmoed R, Caron D, Peace D, Liebes L, Blum RH, Vilcek J. Monocyte activation following systemic administration of granulocyte-macrophage colony-stimulating factor. J Immunother. 1994;15:217–224. doi: 10.1097/00002371-199404000-00008.
    1. Kumar R, Dong Z, Fidler IJ. Differential regulation of metalloelastase activity in murine peritoneal macrophages by granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor. J Immunol. 1996;157:5104–5111.
    1. Dong Z, Kumar R, Yang X, Fidler IJ. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell. 1997;88:801–810. doi: 10.1016/S0092-8674(00)81926-1.
    1. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan RC. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA. 1993;90:3539–3543. doi: 10.1073/pnas.90.8.3539.
    1. Armstrong CA, Botella R, Galloway TH, Murray N, Kramp JM, Song IS, Ansel JC. Antitumor effects of granulocyte-macrophage colony-stimulating factor production by melanoma cells. Cancer Res. 1996;56:2191–2198.
    1. Spitler LE, Grossbard ML, Ernstoff MS, Silver G, Jacobs M, Hayes FA, Soong SJ. Adjuvant therapy of stage III and IV melanoma using granulocyte-macrophage colony stimulating factor. J Clin Oncol. 2000;18:1614–1621.
    1. Lawson DH, Lee SJ, Tarhini AA, Margolin KA, Ernstoff MS, Kirkwood JM (2010) E4697: phase III cooperative group study of yeast-derived granulocyte macrophage colony-stimulating factor (GM-CSF) versus placebo as adjuvant treatment of patients with completely resected stage III–IV melanoma. J Clin Oncol 28:15s, (suppl; abstr 8504)
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumors: Revised RECIST guideline (Version 1.1). Eur J Cancer 45:228–247
    1. Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 1982;38:29–41. doi: 10.2307/2530286.
    1. Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, Moon J, Sondak VK, Atkins MB, Eisenhauer EA, Parulekar W, Markovic SN, Saxman S, Kirkwood JM. Meta-analysis of phase ii cooperative group trials in metastatic stage IV melanoma to determine progression free and overall survival benchmarks for future phase II trials. J Clin Oncol. 2008;26:527–534. doi: 10.1200/JCO.2007.12.7837.
    1. (2010) Melanoma of the Skin. In: AJCC Cancer Staging Manual. Springer, New York, p 325

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