This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, H. X. Articles by Hawkins, M. J. Search for Related Content PubMed PubMed Citation Articles by Chen, H. X. Articles by Hawkins, M. J.

A Safety and Pharmacokinetic Study of a Mixed-Backbone Oligonucleotide (GEM231) Targeting the Type I Protein Kinase A by Two-hour Infusions in Patients with Refractory Solid Tumors¹

Lombardi Cancer Center, Georgetown University Medical Center, Washington DC 20007 [H. X. C., J. L. M., E. N., N. R., W. D., M. J. H.], and Hybridon, Inc., Milford, Massachusetts 01757 [R. R. M., B. D., J. M., M. M.]

GEM231 is a mixed-backbone oligonucleotide targeting the regulatory subunit of type I protein kinase A, which plays an important role in growth and maintenance of malignancies. Preclinically, GEM231 inhibited human cancer xenografts either alone or synergistically with chemotherapeutic agents and has demonstrated an improved metabolic stability and safety profile compared to the first-generation compounds. Objectives of this study were to define the safety profile and pharmacokinetics of GEM231 administered as 2-h IV infusions twice weekly in patients with refractory solid tumors.

Fourteen patients (13 evaluable for safety) received escalating doses of GEM231 at 20–360 mg/m² (2.5–9 mg/kg). Tumor histologies included non-small cell lung cancer, renal cell cancer, sarcoma, and others. The plasma pharmacokinetics of GEM231 were linear and predictable. Maximum plasma concentration (C_max) reached 50–70 µg/ml (8–13 µM) at dose 360 mg/m² and 27–32 µg/ml at dose 240 mg/m². The plasma half-life was about 1.5 h. The only clinical toxicities were transient grade I-II fever and fatigue at doses 240 mg/m². There was no treatment-related complement activation or thrombocytopenia at any dose level, except with the first dose in one patient who had pre-existing borderline thrombocytopenia. Transient activated partial thrombin time prolongation occurred at doses 160 mg/m². Dose-limiting toxicities included transient activated partial thrombin time prolongation (one of three patients at 360 mg/m²) and cumulative reversible transaminase elevation (three of three patients at 360 mg/m² and three of six patients at 240 mg/m² during weeks 3–10). One patient with colon cancer had stabilization of a previously rising carcinoembryonic antigen.

Thus, in this first clinical evaluation of a mixed-backbone oligonucleotide in cancer patients, high plasma concentrations of GEM231 were well tolerated without significant acute toxicities, but prolonged treatment was associated with reversible transaminitis. Although 240 mg/m² by 2-h infusion twice weekly was safe for a 4-week treatment duration, alternative dosing schedules are being tested to minimize the cumulative toxicity, which will be essential to extend the duration of therapy at the highest GEM231 dose tested.

This article has been cited by other articles:

				S. M. Thomas, M. J. Ogagan, M. L. Freilino, S. Strychor, D. R. Walsh, W. E. Gooding, J. R. Grandis, and W. C. Zamboni Antitumor Mechanisms of Systemically Administered Epidermal Growth Factor Receptor Antisense Oligonucleotides in Combination with Docetaxel in Squamous Cell Carcinoma of the Head and Neck Mol. Pharmacol., March 1, 2008; 73(3): 627 - 638. [Abstract] [Full Text] [PDF]

				M. F. McCarty Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy Integr Cancer Ther, December 1, 2004; 3(4): 349 - 380. [Abstract] [PDF]

				Y. S. Cho and Y. S. Cho-Chung Antisense Protein Kinase A RI{alpha} Acts Synergistically with Hydroxycamptothecin to Inhibit Growth and Induce Apoptosis in Human Cancer Cells: Molecular Basis for Combinatorial Therapy Clin. Cancer Res., March 1, 2003; 9(3): 1171 - 1178. [Abstract] [Full Text] [PDF]

				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, February 15, 2002; 99(4): 1150 - 1158. [Abstract] [Full Text] [PDF]

				Y. S. Cho, M.-K. Kim, L. Tan, R. Srivastava, S. Agrawal, and Y. S. Cho-Chung Protein Kinase A RI{alpha} Antisense Inhibition of PC3M Prostate Cancer Cell Growth: Bcl-2 Hyperphosphorylation, Bax Up-Regulation, and Bad-Hypophosphorylation Clin. Cancer Res., February 1, 2002; 8(2): 607 - 614. [Abstract] [Full Text] [PDF]

				G. Tortora, R. Caputo, V. Damiano, G. Fontanini, D. Melisi, B. Maria Veneziani, F. Zunino, A. R. Bianco, and F. Ciardiello Oral Administration of a Novel Taxane, an Antisense Oligonucleotide Targeting Protein Kinase A, and the Epidermal Growth Factor Receptor Inhibitor Iressa Causes Cooperative Antitumor and Antiangiogenic Activity Clin. Cancer Res., December 1, 2001; 7(12): 4156 - 4163. [Abstract] [Full Text] [PDF]

				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 Clin. Cancer Res., August 1, 2001; 7(8): 2537 - 2544. [Abstract] [Full Text] [PDF]

				Y. S. Cho, M.-K. Kim, C. Cheadle, C. Neary, K. G. Becker, and Y. S. Cho-Chung Antisense DNAs as multisite genomic modulators identified by DNA microarray PNAS, July 24, 2001; (2001) 171314398. [Abstract] [Full Text] [PDF]

				C. Bianco, R. Bianco, G. Tortora, V. Damiano, P. Guerrieri, P. Montemaggi, J. Mendelsohn, S. De Placido, A. R. Bianco, and F. Ciardiello Antitumor Activity of Combined Treatment of Human Cancer Cells with Ionizing Radiation and Anti-Epidermal Growth Factor Receptor Monoclonal Antibody C225 plus Type I Protein Kinase A Antisense Oligonucleotide Clin. Cancer Res., November 1, 2000; 6(11): 4343 - 4350. [Abstract] [Full Text] [PDF]

				B. H. Dvorchik and J. K. Marquis Disposition and Toxicity of a Mixed Backbone Antisense Oligonucleotide, Targeted against Human Cytomegalovirus, after Intravitreal Injection of Escalating Single Doses in the Rabbit Drug Metab. Dispos., October 1, 2000; 28(10): 1255 - 1261. [Abstract] [Full Text] [PDF]

				G. Tortora, R. Bianco, V. Damiano, G. Fontanini, S. De Placido, A. R. Bianco, and F. Ciardiello Oral Antisense that Targets Protein Kinase A Cooperates with Taxol and Inhibits Tumor Growth, Angiogenesis, and Growth Factor Production Clin. Cancer Res., June 1, 2000; 6(6): 2506 - 2512. [Abstract] [Full Text]

				Y. S. Cho, M.-K. Kim, C. Cheadle, C. Neary, K. G. Becker, and Y. S. Cho-Chung Antisense DNAs as multisite genomic modulators identified by DNA microarray PNAS, August 14, 2001; 98(17): 9819 - 9823. [Abstract] [Full Text] [PDF]