Originally published as JCO Early Release 10.1200/JCO.2005.02.4364 on September 26 2005

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 Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by O'Brien, S. M. Articles by Rai, K. R. Search for Related Content PubMed PubMed Citation Articles by O'Brien, S. M. Articles by Rai, K. R. Social Bookmarking                            What's this?

Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia

From the M.D. Anderson Cancer Center, Houston; US Oncology, Dallas, TX; Genta Incorporated, Berkeley Heights, NJ; Long Island Jewish Medical Center, New Hyde Park, NY; Moscow Regional Clinical Research Institute; and Russian Academy of Medical Sciences, Moscow, Russia

Address reprint requests to Susan M. O'Brien, MD, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030-7305; e-mail: sobrien{at}mdanderson.org

PURPOSE: To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL).

PATIENTS AND METHODS: Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients.

RESULTS: Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance.

CONCLUSION: Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

Supported in part by Genta Incorporated, Berkeley Heights, NJ.

Presented in part at the 43rd Annual Meeting of the American Society of Hematology, Orlando, FL, December 7-11, 2001, and the 44th Annual Meeting of the American Society of Hematology, Philadelphia, PA, December 6-10, 2002.

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				S. O'Brien, J. O. Moore, T. E. Boyd, L. M. Larratt, A. B. Skotnicki, B. Koziner, A. A. Chanan-Khan, J. F. Seymour, J. Gribben, L. M. Itri, et al. 5-Year Survival in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia in a Randomized, Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen J. Clin. Oncol., November 1, 2009; 27(31): 5208 - 5212. [Abstract] [Full Text] [PDF]

				G. Aue, N. Njuguna, X. Tian, S. Soto, T. Hughes, B. Vire, K. Keyvanfar, F. Gibellini, J. Valdez, C. Boss, et al. Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia Haematologica, September 1, 2009; 94(9): 1266 - 1273. [Abstract] [Full Text] [PDF]

				M. H. Kang and C. P. Reynolds Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy Clin. Cancer Res., February 15, 2009; 15(4): 1126 - 1132. [Abstract] [Full Text] [PDF]

				E. G.E. de Vries and S. de Jong Exploiting the Apoptotic Route for Cancer Treatment: A Single Hit Will Rarely Result in a Home Run J. Clin. Oncol., November 10, 2008; 26(32): 5151 - 5153. [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., October 1, 2008; 19(10): 1698 - 1705. [Abstract] [Full Text] [PDF]

				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]

				F. Jia, S. D. Figueroa, F. Gallazzi, B. S. Balaji, M. Hannink, S. Z. Lever, T. J. Hoffman, and M. R. Lewis Molecular Imaging of bcl-2 Expression in Small Lymphocytic Lymphoma Using 111In-Labeled PNA-Peptide Conjugates J. Nucl. Med., March 1, 2008; 49(3): 430 - 438. [Abstract] [Full Text] [PDF]

				S. O'Brien New Agents in the Treatment of CLL Hematology, January 1, 2008; 2008(1): 457 - 464. [Abstract] [Full Text] [PDF]

				W. G. Wierda Treatments for Patients with Chronic Lymphocytic Leukemia ASCO Educational Book, January 1, 2008; 2008(1): 297 - 305. [Abstract] [Full Text] [PDF]

				S. R. Rheingold, M. D. Hogarty, S. M. Blaney, J. A. Zwiebel, C. Sauk-Schubert, R. Chandula, M. D. Krailo, and P. C. Adamson Phase I Trial of G3139, a bcl-2 Antisense Oligonucleotide, Combined With Doxorubicin and Cyclophosphamide in Children With Relapsed Solid Tumors: A Children's Oncology Group Study J. Clin. Oncol., April 20, 2007; 25(12): 1512 - 1518. [Abstract] [Full Text] [PDF]

				S. O'Brien, J. O. Moore, T. E. Boyd, L. M. Larratt, A. Skotnicki, B. Koziner, A. A. Chanan-Khan, J. F. Seymour, R. G. Bociek, S. Pavletic, et al. Randomized Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen Sodium (Bcl-2 antisense) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia J. Clin. Oncol., March 20, 2007; 25(9): 1114 - 1120. [Abstract] [Full Text] [PDF]

				H. Nuckel, U. H. Frey, M. Bau, L. Sellmann, J. Stanelle, J. Durig, K.-H. Jockel, U. Duhrsen, and W. Siffert Association of a novel regulatory polymorphism (-938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia Blood, January 1, 2007; 109(1): 290 - 297. [Abstract] [Full Text] [PDF]

				L. Chin, L. A. Garraway, and D. E. Fisher Malignant melanoma: genetics and therapeutics in the genomic era. Genes & Dev., August 15, 2006; 20(16): 2149 - 2182. [Abstract] [Full Text] [PDF]

				W. G. Wierda Current and Investigational Therapies for Patients with CLL Hematology, January 1, 2006; 2006(1): 285 - 294. [Abstract] [Full Text] [PDF]