Abstract
Purpose
RPI.4610 (ANGIOZYME) is a chemically stabilized ribozyme targeting vascular endothelial growth factor receptor 1. The purpose of this study was to evaluate the safety and pharmacokinetics of RPI.4610 in combination with carboplatin and paclitaxel in patients with advanced solid tumors.
Methods
The study used a sequential treatment design evaluating a single dose level for all three drugs: paclitaxel 175 mg m−2 and carboplatin AUC=6 on day 1 of a 21-day cycle, and RPI.4610 100 mg m−2 day−1 beginning on day 8 and continuing daily thereafter. Pharmacokinetic samples were drawn on day 1 of courses 1 (chemotherapy alone) and 2 (chemotherapy+RPI.4610), and on day 8 of course 1 (RPI.4610 alone). Ratios were generated by comparing the pharmacokinetic parameters for the combination of carboplatin with paclitaxel when administered alone or together with RPI.4610.
Results
Twelve patients were enrolled in this trial and received two to six courses of treatment each. The most common grade 3–4 toxicities were neutropenia (three patients), thrombocytopenia (three patients), pain (three patients), anemia (two patients) and fatigue (two patients). The ratio of the mean maximum plasma concentration (Cmax) for carboplatin when administered with paclitaxel alone versus when administered with paclitaxel and RPI.4610 was 1.07 (90% confidence interval, 0.77–1.37). Similarly, the ratio of the mean AUC0-last for carboplatin was 1.04 (0.73–1.35). For paclitaxel the ratio of the mean Cmax when administered with carboplatin alone versus with carboplatin and RPI.4610 was 1.17 (1.03–1.31), and the ratio of the mean AUC0–last was 1.17 (1.04–1.30). Objective tumor responses were observed and included one patient with a complete response (bladder cancer) and one patient with a partial response (esophageal cancer).
Conclusions
These results indicate that RPI.4610, carboplatin, and paclitaxel can be administered safely in combination without substantial pharmacokinetic interactions.
Similar content being viewed by others
References
Adjei AA, Dy GK, Erlichman C et al (2003) A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, in combination with gemcitabine in patients with advanced cancer. Clin Cancer Res 9:115–123
Akerley W, Herndon JE, Egorin MJ et al (2003) Weekly, high-dose paclitaxel in advanced lung carcinoma: a phase II study with pharmacokinetics by the Cancer and Leukemia Group B. Cancer 97:2480–2486
Allain P, Berre S, Mauras Y, Le Bouil A (1992) Evaluation of inductively coupled mass spectrometry for the determination of platinum in plasma. Biol Mass Spectrom 21:141–143
Bamberger ES, Perrett CW (2002) Angiogenesis in epithelian ovarian cancer. Mol Pathol 55:348–359
Bauer J, Morrison B, Oates R et al (2003) ANGIOZYME and interferon-α2b synergistically inhibit tumor angiogenesis. Proc Am Assoc Cancer Res 44 (Abstr 1159)
Buoen C, Holm S, Thomsen MS (2003) Evaluation of the cohort size in phase I dose escalation trials based on laboratory data. J Clin Pharmacol 43:470–476
Herbst RS, Takeuchi H, Teicher BA (1998) Paclitaxel/carboplatin administration along with antiangiogenic therapy in non-small-cell lung and breast carcinoma models. Cancer Chemother Pharmacol 41:497–504
Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342
Jackson E, Sweedler D, Hartsough K et al (2002) Assessment of pharmacokinetic drug interactions between carboplatin and ANGIOZYME in vivo. Proc Am Assoc Cancer Res 43 (Abstr 1927)
Margolin K, Gordon MS, Holmgren E et al (2001) Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol 19:851–856
Meert AP, Paesmans M, Martin B et al (2002) The role of microvessel density on the survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 87:694–701
Parry TJ, Cushman C, Gallegos AM et al (1999) Bioactivity of anti-angiogenic ribozymes targeting Flt-1 and KDR mRNA. Nucleic Acids Res 27:2569–2577
Pavco PA, Bouhana KS, Gallegos AM et al (2000) Antitumor and antimetastatic activity of ribozymes targeting the messenger RNA of vascular endothelial growth factor receptors. Clin Cancer Res 6:2094–2103
Pivot X, Cals L, Cupissol D et al (2001) Phase II trial of a paclitaxel-carboplatin combination in recurrent squamous cell carcinoma of the head and neck. Oncology 60:66–71
Royer I, Alvinerie P, Armand JP et al (1995) Paclitaxel metabolites in human plasma and urine: identification of 6 alpha-hydroxytaxol, 7-epitaxol and taxol hydrolysis products using liquid chromatography/atmospheric-pressure chemical ionization mass spectrometry. Rapid Commun Mass Spectrom 9:495–502
Rudin CM, Kozloff M, Hoffman PC et al (2004) Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J Clin Oncol 22:1110–1117
Sandberg JA, Parker VP, Blanchard KS et al (2000) Pharmacokinetics and tolerability of an antiangiogenic ribozyme (ANGIOZYME) in healthy volunteers. J Clin Pharmacol 40:1462–1469
Sandberg JA, Sproul CD, Blanchard KS et al (2000) Acute toxicology and pharmacokinetic assessment of a ribozyme (ANGIOZYME) targeting vascular endothelial growth factor receptor mRNA in the cynomolgus monkey. Antisense Nucleic Acid Drug Dev 10:153–162
U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research (1999) In vivo drug metabolism/drug interaction studies—study design, data analysis, and recommendations for dosing and labeling
Venook A, Hurwitz H, Cunningham C et al (2003) Relationship of clinical outcome in metastatic colorectal carcinoma to levels of soluble VEGFR-1: results of a phase II trial of a ribozyme targeting the pre-mRNA of VEGFR-1 (angiozyme) in combination with chemotherapy. Proc Am Soc Clin Oncol 22 (Abstr 1025)
Weng DE, Weiss P, Kellackey C et al (2001) Angiozyme pharmacokinetic and safety results: a phase I/II study in patients with refractory solid tumors. Proc Am Soc Clin Oncol 20 (Abstr 393)
Acknowledgements
This trial was supported by Sirna Therapeutics, Chiron, and NIH Grant RR00095. We thank Drs Jordan D. Berlin and Bruce J. Roth (Vanderbilt-Ingram Cancer Center), Dr Andrew S. Pierson and Martha S. Persky, R.N. (University of Colorado Cancer Center) for managing all clinical aspects of some study patients. We are also grateful to Drs Gary S. Gordon and Vann P. Parker for their help in performing pharmacokinetic analyses.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kobayashi, H., Gail Eckhardt, S., Lockridge, J.A. et al. Safety and pharmacokinetic study of RPI.4610 (ANGIOZYME), an anti-VEGFR-1 ribozyme, in combination with carboplatin and paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 56, 329–336 (2005). https://doi.org/10.1007/s00280-004-0968-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-004-0968-x