Journal of Clinical Oncology, Vol 18, Issue 9
(May), 2000: 1812-1823
© 2000 American Society for Clinical Oncology
Phase I Clinical and Pharmacokinetic Study of Bcl-2 Antisense Oligonucleotide Therapy in Patients With Non-Hodgkin’s Lymphoma
By Justin S. Waters,
Andrew Webb,
David Cunningham,
Paul A. Clarke,
Florence Raynaud,
Francesca di Stefano,
Finbarr E. Cotter
From the Lymphoma Unit, Royal Marsden Hospital, and Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, and Institute of Child Health, London, United Kingdom.
Address reprint requests to David Cunningham, MD, Department of Medicine, Royal Marsden Hospital, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom; email dcunn{at}icr.ac.uk
PURPOSE: To evaluate the pharmacokinetics and toxicity of an antisense oligonucleotide targeting bcl-2 in patients with non-Hodgkin’s lymphoma (NHL) and to determine efficacy using clinical and biologic end points.
PATIENTS AND METHODS: Twenty-one patients with Bcl-2–positive relapsed NHL received a 14-day subcutaneous infusion of G3139, an 18-mer phosphorothioate oligonucleotide complementary to the first six codons of the bcl-2 open reading frame. Plasma pharmacokinetics were measured by anion exchange high-performance liquid chromatography. Response was assessed by computed tomography. Changes in Bcl-2 expression were measured by fluorescence-activated cell sorting of patients’ tumor samples.
RESULTS: Eight cohorts of patients received doses between 4.6 and 195.8 mg/m2/d. No significant systemic toxicity was seen at doses up to 110.4 mg/m2/d. All patients displayed skin inflammation at the subcutaneous infusion site. Dose-limiting toxicities were thrombocytopenia, hypotension, fever, and asthenia. The maximum-tolerated dose was 147.2 mg/m2/d. Plasma levels of G3139 equivalent to the efficacious plasma concentration in in vivo models were produced with doses above 36.8 mg/m2/d. Plasma levels associated with dose-limiting toxicity were greater than 4 µg/mL. By standard criteria, there was one complete response, 2 minor responses, nine cases of stable disease, and nine cases of progressive disease. Bcl-2 protein was reduced in seven of 16 assessable patients. This reduction occurred in tumor cells derived from lymph nodes in two patients and from peripheral blood or bone marrow mononuclear cell populations in the remaining five patients.
CONCLUSION: Bcl-2 antisense therapy is feasible and shows potential for antitumor activity in NHL. Downregulation of Bcl-2 protein suggests a specific antisense mechanism.
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[Abstract]
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W. R. Smythe, I. Mohuiddin, M. Ozveran, and X. X. Cao
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[Abstract]
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F. Ciardiello and G. Tortora
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Ann. Onc.,
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C. M. Rudin, G. A. Otterson, A. M. Mauer, M. A. Villalona-Calero, R. Tomek, B. Prange, C. M. George, L. Szeto, and E. E. Vokes
A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer
Ann. Onc.,
April 1, 2002;
13(4):
539 - 545.
[Abstract]
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R. Mohammad, Y. Abubakr, M. Dan, A. Aboukameel, C. Chow, A. Mohamed, N. Hamdy, and A. Al-Katib
Bcl-2 Antisense Oligonucleotides Are Effective against Systemic but not Central Nervous System Disease in Severe Combined Immunodeficient Mice Bearing Human t(14;18) Follicular Lymphoma
Clin. Cancer Res.,
April 1, 2002;
8(4):
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[Abstract]
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M. J. Morris, W. P. Tong, C. Cordon-Cardo, M. Drobnjak, W. K. Kelly, S. F. Slovin, K. L. Terry, K. Siedlecki, P. Swanson, M. Rafi, et al.
Phase I Trial of BCL-2 Antisense Oligonucleotide (G3139) Administered by Continuous Intravenous Infusion in Patients with Advanced Cancer
Clin. Cancer Res.,
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[Abstract]
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S. M. Luger, S. G. O'Brien, J. Ratajczak, M. Z. Ratajczak, R. Mick, E. A. Stadtmauer, P. C. Nowell, J. M. Goldman, and A. M. Gewirtz
Oligodeoxynucleotide-mediated inhibition of c-myb gene expression in autografted bone marrow: a pilot study
Blood,
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[Abstract]
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R. S. Finley
New Directions in the Treatment of Cancer: Inhibition of Signal Transduction
Journal of Pharmacy Practice,
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[Abstract]
[PDF]
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A. D. Schimmer, D. W. Hedley, L. Z. Penn, and M. D. Minden
Receptor- and mitochondrial-mediated apoptosis in acute leukemia: a translational view
Blood,
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K. N. Chi, M. E. Gleave, R. Klasa, N. Murray, C. Bryce, D. E. Lopes de Menezes, S. D'Aloisio, and A. W. Tolcher
A Phase I Dose-finding Study of Combined Treatment with an Antisense Bcl-2 Oligonucleotide (Genasense) and Mitoxantrone in Patients with Metastatic Hormone-refractory Prostate Cancer
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[Abstract]
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S. Talapatra and C. B. Thompson
Growth Factor Signaling in Cell Survival: Implications for Cancer Treatment
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H. Roh, D. W. Green, C. B. Boswell, J. A. Pippin, and J. A. Drebin
Suppression of {beta}-Catenin Inhibits the Neoplastic Growth of APC-Mutant Colon Cancer Cells
Cancer Res.,
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M. Gorschluter, C. Ziske, A. Glasmacher, and I. G. H. Schmidt-Wolf
Current Clinical and Laboratory Strategies to Augment the Efficacy of Immunotherapy in Multiple Myeloma
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G. Tortora, R. Caputo, V. Damiano, R. Bianco, G. Fontanini, S. Cuccato, S. De Placido, A. R. Bianco, and F. Ciardiello
Combined Blockade of Protein Kinase A and Bcl-2 by Antisense Strategy Induces Apoptosis and Inhibits Tumor Growth and Angiogenesis
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J. Sjostrom and J. Bergh
How apoptosis is regulated, and what goes wrong in cancer
BMJ,
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V. Poulaki, N. Mitsiades, M. E. Romero, and M. Tsokos
Fas-mediated Apoptosis in Neuroblastoma Requires Mitochondrial Activation and Is Inhibited by FLICE Inhibitor Protein and bcl-2
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R. J. Klasa, A. F. List, and B. D. Cheson
Rational Approaches to Design of Therapeutics Targeting Molecular Markers
Hematology,
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[Abstract]
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A. M. Gewirtz
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N. C. Gorin, E. Estey, R. J. Jones, H. I. Levitsky, I. Borrello, and S. Slavin
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Hematology,
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[Abstract]
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