Originally published as JCO Early Release 10.1200/JCO.2006.06.0483 on September 11 2006

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bedikian, A. Y. Articles by Haluska, F. G. Search for Related Content PubMed PubMed Citation Articles by Bedikian, A. Y. Articles by Haluska, F. G. Related Articles Related Editorial Related Correspondence

Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: The Oblimersen Melanoma Study Group

Agop Y. Bedikian, Michael Millward, Hubert Pehamberger, Robert Conry, Martin Gore, Uwe Trefzer, Anna C. Pavlick, Ronald DeConti, Evan M. Hersh, Peter Hersey, John M. Kirkwood, Frank G. Haluska

From the University of Texas M.D. Anderson Cancer Center, Houston, TX; Sydney Cancer Centre and Sydney Melanoma Unit, Sydney, Australia; Division of General Dermatology, Medical University of Vienna, Vienna, Austria; University of Alabama at Birmingham, Hematology/Oncology, Birmingham, AL; Royal Marsden Hospital, London, United Kingdom; Klinik fur Dermatologie, Venerologie, und Allergologie mit Asthmapoliklinik, Charité Universitätsmedizin Berlin, Berlin, Germany; New York University School of Medicine, New York, NY; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Arizona Cancer Center, Tucson, AZ; Newcastle Mater Misericordiae Hospital, Waratah, Australia; University of Pittsburgh Cancer Institute, Pittsburgh, PA; and Tufts-New England Medical Center, Boston, MA

Address reprint requests to Frank G. Haluska, MD, PhD, Tufts-New England Medical Center, 750 Washington St, Box 6626, Boston, MA 02111; e-mail: FHaluska{at}tufts-nemc.org

PURPOSE: Chemotherapy resistance in melanoma has been linked to antiapoptotic effects mediated by Bcl-2 protein. We evaluated whether targeting Bcl-2 using an antisense oligonucleotide (oblimersen sodium) could improve the efficacy of systemic chemotherapy in patients with advanced melanoma.

PATIENTS AND METHODS: We randomly assigned chemotherapy-naïve patients with advanced melanoma to treatment with dacarbazine (1,000 mg/m²) alone or preceded by a 5-day continuous intravenous infusion of oblimersen sodium (7 mg/kg/d) every 3 weeks for up to eight cycles. Patients were stratified by Eastern Cooperative Oncology Group performance status, liver metastases, disease site, and serum lactate dehydrogenase (LDH). The primary efficacy end point was overall survival.

RESULTS: Among 771 patients randomly assigned, the addition of oblimersen to dacarbazine yielded a trend toward improved survival at 24-month minimum follow-up (median, 9.0 v 7.8 months; P = .077) and significant increases in progression-free survival (median, 2.6 v 1.6 months; P < .001), overall response (13.5% v 7.5%; P = .007), complete response (2.8% v 0.8%), and durable response (7.3% v 3.6%; P = .03). A significant interaction between baseline serum LDH and treatment was observed; oblimersen significantly increased survival in patients whose baseline serum LDH was not elevated (median overall survival, 11.4 v 9.7 months; P = .02). Neutropenia and thrombocytopenia were increased in the oblimersen-dacarbazine group; however, there was no increase in serious infections or bleeding events.

CONCLUSION: The addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes in patients with advanced melanoma and increased overall survival in patients without an elevated baseline serum LDH.

published online ahead of print at www.jco.org on September 11, 2006.

Supported by Genta, Inc.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Related Editorial

• Reaching First Base in the Treatment of Metastatic Melanoma
  Alexander M.M. Eggermont
  JCO 2006 24: 4673-4674 [Full Text]

Related Correspondence

• Molecular Classification of Patients With Malignant Melanoma for New Therapeutic Strategies
  Giuseppe Palmieri, Milena Casula, Paolo A. Ascierto, Francesco Tanda, and Antonio Cossu
  JCO 2007 25: 20-21 [Full Text]
• Molecular Classification of Patients With Malignant Melanoma for New Therapeutic Strategies
  Giuseppe Palmieri, Milena Casula, Paolo A. Ascierto, Francesco Tanda, and Antonio Cossu
  JCO 2007 25: 20-21 [Full Text]

This article has been cited by other articles:

				L. A. Andritsos, A. J. Johnson, G. Lozanski, W. Blum, C. Kefauver, F. Awan, L. L. Smith, R. Lapalombella, S. E. May, C. A. Raymond, et al. Higher Doses of Lenalidomide Are Associated With Unacceptable Toxicity Including Life-Threatening Tumor Flare in Patients With Chronic Lymphocytic Leukemia J. Clin. Oncol., May 20, 2008; 26(15): 2519 - 2525. [Abstract] [Full Text] [PDF]

				J. Rom, G. von Minckwitz, W. Eiermann, M. Sievert, B. Schlehe, F. Marme, F. Schuetz, A. Scharf, M. Eichbaum, H.-P. Sinn, et al. Oblimersen combined with docetaxel, adriamycin and cyclophosphamide as neo-adjuvant systemic treatment in primary breast cancer: final results of a multicentric phase I study Ann. Onc., May 13, 2008; (2008) mdn280v1. [Abstract] [Full Text] [PDF]

				D. F. McDermott, J. A. Sosman, R. Gonzalez, F. S. Hodi, G. P. Linette, J. Richards, J. W. Jakub, M. Beeram, S. Tarantolo, S. Agarwala, et al. Double-Blind Randomized Phase II Study of the Combination of Sorafenib and Dacarbazine in Patients With Advanced Melanoma: A Report From the 11715 Study Group J. Clin. Oncol., May 1, 2008; 26(13): 2178 - 2185. [Abstract] [Full Text] [PDF]

				G. Liu, J. Kolesar, D. G. McNeel, C. Leith, K. Schell, J. Eickhoff, F. Lee, A. Traynor, R. Marnocha, D. Alberti, et al. A Phase I Pharmacokinetic and Pharmacodynamic Correlative Study of the Antisense Bcl-2 Oligonucleotide G3139, in Combination with Carboplatin and Paclitaxel, in Patients with Advanced Solid Tumors Clin. Cancer Res., May 1, 2008; 14(9): 2732 - 2739. [Abstract] [Full Text] [PDF]

				C. M. Rudin, R. Salgia, X. Wang, L. D. Hodgson, G. A. Masters, M. Green, and E. E. Vokes Randomized Phase II Study of Carboplatin and Etoposide With or Without the bcl-2 Antisense Oligonucleotide Oblimersen for Extensive-Stage Small-Cell Lung Cancer: CALGB 30103 J. Clin. Oncol., February 20, 2008; 26(6): 870 - 876. [Abstract] [Full Text] [PDF]

				A. Testori, J. Richards, E. Whitman, G. B. Mann, J. Lutzky, L. Camacho, G. Parmiani, G. Tosti, J. M. Kirkwood, A. Hoos, et al. Phase III Comparison of Vitespen, an Autologous Tumor-Derived Heat Shock Protein gp96 Peptide Complex Vaccine, With Physician's Choice of Treatment for Stage IV Melanoma: The C-100-21 Study Group J. Clin. Oncol., February 20, 2008; 26(6): 955 - 962. [Abstract] [Full Text] [PDF]

				D. S. Ziegler, A. L. Kung, and M. W. Kieran Anti-Apoptosis Mechanisms in Malignant Gliomas J. Clin. Oncol., January 20, 2008; 26(3): 493 - 500. [Abstract] [Full Text] [PDF]

				N. J. Ives, R. L. Stowe, P. Lorigan, and K. Wheatley Chemotherapy Compared With Biochemotherapy for the Treatment of Metastatic Melanoma: A Meta-Analysis of 18 Trials Involving 2,621 Patients J. Clin. Oncol., December 1, 2007; 25(34): 5426 - 5434. [Abstract] [Full Text] [PDF]

				F. Lefranc, V. Facchini, and R. Kiss Proautophagic Drugs: A Novel Means to Combat Apoptosis-Resistant Cancers, with a Special Emphasis on Glioblastomas Oncologist, December 1, 2007; 12(12): 1395 - 1403. [Abstract] [Full Text] [PDF]

				R. Scatena, P. Bottoni, G. Botta, G. E. Martorana, and B. Giardina The role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topic Am J Physiol Cell Physiol, July 1, 2007; 293(1): C12 - C21. [Abstract] [Full Text] [PDF]

				G. Palmieri, M. Casula, P. A. Ascierto, F. Tanda, and A. Cossu Molecular Classification of Patients With Malignant Melanoma for New Therapeutic Strategies J. Clin. Oncol., June 1, 2007; 25(16): e20 - e21. [Full Text] [PDF]

				S. Mena, M. Benlloch, A. Ortega, J. Carretero, E. Obrador, M. Asensi, I. Petschen, B. D. Brown, and J. M. Estrela Bcl-2 and Glutathione Depletion Sensitizes B16 Melanoma to Combination Therapy and Eliminates Metastatic Disease Clin. Cancer Res., May 1, 2007; 13(9): 2658 - 2666. [Abstract] [Full Text] [PDF]

				Technical Knockdown in Melanoma Journal Watch Dermatology, December 8, 2006; 2006(1208): 1 - 1. [Full Text]

				A. M.M. Eggermont Reaching First Base in the Treatment of Metastatic Melanoma J. Clin. Oncol., October 10, 2006; 24(29): 4673 - 4674. [Full Text] [PDF]