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 Mani, S. Articles by Ratain, M. J. Search for Related Content PubMed PubMed Citation Articles by Mani, S. Articles by Ratain, M. J.

Phase I Clinical and Pharmacokinetic Study of Protein Kinase C- Antisense Oligonucleotide ISIS 3521 Administered in Combination with 5-Fluorouracil and Leucovorin in Patients with Advanced Cancer¹

Department of Medicine, Section of Hematology-Oncology, Cancer Research Center [S. M., C. M. R., K. K., H. L. K., M. J. R.] and Committee on Clinical Pharmacology [M. J. R.], University of Chicago, Chicago, Illinois 60637, and ISIS Pharmaceuticals, Inc., Carlsbad, California 92008 [J. T. H., R. S. G., F. A. D.]

The present study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PKs), and antitumor activity of the protein kinase C- antisense oligonucleotide ISIS 3521 (ISIS Pharmaceuticals, Inc., Carlsbad, CA) when administered in combination with 5-fluorouracil (5-FU) and leucovorin (LV). Patients with refractory solid tumors received ISIS 3521 as a 21-day continuous infusion administered simultaneously with 5-FU and LV given daily for 5 days repeated every 4–5 weeks (one cycle). 5-FU and ISIS 3521 PK analysis were performed on samples taken during the first cycle in all patients. Fifteen patients received ISIS 3521 at one of three dose levels: (a) 1.0 (n = 3 patients); (b) 1.5 (n = 3 patients); and (c) 2.0 (n = 9 patients) mg/kg/day. All patients simultaneously received 5-FU (425 mg/m²/day) and LV (20 mg/m²/day) for 5 consecutive days. Grade 1–2 toxicities included alopecia, fatigue, mucositis, diarrhea, anorexia, nausea/vomiting, and tumor pain. One patient had grade 3 chest pain considered to be related to 5-FU therapy, another patient had dose-limiting grade 3 mucositis resolving in <7 days, and one patient with a history of gastritis had an acute upper gastrointestinal bleed thought to be 5-FU-induced toxicity. Five patients developed cycle 1 grade 4 neutropenia, which resolved without colony-stimulating factors before the next treatment cycle. There were no effects on prothrombin time and activated partial thromboplastin time. A clinically defined MTD was not reached. The character and severity of these toxicities do not seem to be dose related, and, as such, there was no classical dose-limiting toxicity defining the MTD. ISIS 3521 PKs in the presence of 5-FU was consistent with those reported previously. 5-FU PK parameters were also similar in the presence or absence of ISIS 3521. Six of 14 patients (43%) across all dose cohorts had an improvement in measurable tumor response ranging from minor reduction in tumor size (4 patients) to objective partial response (>50% reduction in tumor size, 2 patients). ISIS 3521 is tolerable at its recommended single-agent dose when given with 5-FU and LV. There is no apparent PK interaction between ISIS 3521 and 5-FU and LV. Antitumor activity was observed with the combination; however, it is uncertain whether clinical activity is a result of enhanced drug interaction. Our study warrants further exploration of efficacy in a Phase II and/or Phase III clinical trial setting.

This article has been cited by other articles:

				H. Oster and M. Leitges Protein Kinase C {alpha} but not PKC{zeta} Suppresses Intestinal Tumor Formation in ApcMin/+ Mice. Cancer Res., July 15, 2006; 66(14): 6955 - 6963. [Abstract] [Full Text] [PDF]

				T. Jelacic and D. Linnekin PKC{delta} plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant Blood, March 1, 2005; 105(5): 1923 - 1929. [Abstract] [Full Text] [PDF]

				R. B. Bhisitkul, G. S. Robinson, R. S. Moulton, K. P. Claffey, E. S. Gragoudas, and J. W. Miller An Antisense Oligodeoxynucleotide Against Vascular Endothelial Growth Factor in a Nonhuman Primate Model of Iris Neovascularization Arch Ophthalmol, February 1, 2005; 123(2): 214 - 219. [Abstract] [Full Text] [PDF]

				S. A. Grossman, J. B. Alavi, J. G. Supko, K. A. Carson, R. Priet, F. A. Dorr, J. S. Grundy, and J. T. Holmlund Efficacy and toxicity of the antisense oligonucleotide aprinocarsen directed against protein kinase C-{alpha} delivered as a 21-day continuous intravenous infusion in patients with recurrent high-grade astrocytomas Neuro-oncol, January 1, 2005; 7(1): 32 - 40. [Abstract] [PDF]

				S. Rao, D. Watkins, D. Cunningham, D. Dunlop, P. Johnson, P. Selby, B. W. Hancock, C. Fegan, D. Culligan, S. Schey, et al. Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C alpha, in patients with previously treated low-grade non-Hodgkin's lymphoma Ann. Onc., September 1, 2004; 15(9): 1413 - 1418. [Abstract] [Full Text] [PDF]

				S. Goel, K. Desai, A. Bulgaru, A. Fields, G. Goldberg, S. Agrawal, R. Martin, M. Grindel, and S. Mani A Safety Study of a Mixed-backbone Oligonucleotide (GEM231) Targeting the Type I Regulatory Subunit {alpha} of Protein Kinase A Using a Continuous Infusion Schedule in Patients with Refractory Solid Tumors Clin. Cancer Res., September 15, 2003; 9(11): 4069 - 4076. [Abstract] [Full Text] [PDF]