Summary
Purpose To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetic profile of ispinesib when administered as a 1-h intravenous infusion weekly for three consecutive weeks of a 28 day treatment period to patients with advanced solid tumors. Experimental Design Thirty patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase at doses ranging from 1–8 mg/m2/week. Pharmacokinetic samples, skin punch biopsies, and tumor biopsies (in patients with accessible tumor) were obtained during cycle 1 of treatment. Disease assessment was performed every two treatment cycles. Results The MTD was defined as 7 mg/m2 administered as a 1-h infusion weekly for three consecutive weeks of a 28 day schedule. The MTD was exceeded at 8 mg/m2 due to DLTs of grade 2 (one patient) and grade 3 neutropenia (one patient) that resulted in the inability to administer the Day 15 dose in Cycle 1. The neutrophil nadir occurred at approximately Day 8 with a 3–7 day recovery period. The most common toxicities were nausea, diarrhea, fatigue, and neutropenia. Alopecia, mucositis, and neuropathy were not observed. Stable disease was reported as the best response to treatment in nine patients. Conclusion The recommended dose of ispinesib is 7 mg/m2 over 1 h weekly for three consecutive weeks of a 28 day treatment cycle.
Similar content being viewed by others
References
Wood KW, Cornwell WD, Jackson JR (2001) Past and future of the mitotic spindle as an oncology target. Curr Opin Pharmacol 1:370–377
Miglarese MR, Carlson RO (2006) Development of new cancer therapeutic agents targeting mitosis. Expert Opin Investig Drugs 15:1411–1425
Bergnes G, Brejc K, Belmont L (2005) Mitotic kinesins: prospects for antimitotic drug discovery. Current topics in medicinal chemistry 5:127–145
Kapitein LC, Peterman EJ, Kwok BH, Kim JH, Kapoor TM, Schmidt CF (2005) The bipolar mitotic kinesin Eg5 moves on both microtubules that it crosslinks. Nature 435:114–118
Blangy A, Lane HA, d’Herin P, Harper M, Kress M, Nigg EA (1995) Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83:1159–1169
Kashina AS, Baskin RJ, Cole DG, Wedaman KP, Saxton WM, Scholey JM (1996) A bipolar kinesin. Nature 379:270–272
Tao W, South VJ, Diehl RE et al (2007) An inhibitor of the kinesin spindle protein activates the intrinsic apoptotic pathway independently of p53 and de novo protein synthesis. Mol Cell Biol 27:689–698
Tao W, South VJ, Zhang Y et al (2005) Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell 8:49–59
Hedge P, Cogswell J, Carrick K et al (2003) Differential gene expression analysis of kinesin spindle protein in human solid tumors. Proc Am Assoc Cancer Res 22:535
Sakowicz R, Finer JT, Beraud C et al (2004) Antitumor activity of a kinesin inhibitor. Cancer Res 64:3276–3280
Muller C, Gross D, Sarli V et al (2007) Inhibitors of kinesin Eg5: antiproliferative activity of monastrol analogues against human glioblastoma cells. Cancer Chemother Pharmacol 59:157–164
Marcus AI, Peters U, Thomas SL et al (2005) Mitotic kinesin inhibitors induce mitotic arrest and cell death in Taxol-resistant and -sensitive cancer cells. J Biol Chem 280:11569–11577
Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ (2000) Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J Cell Biol 150:975–988
Lad L, Luo L, Carson JD et al (2008) Mechanism of inhibition of human KSP by ispinesib. Biochemistry 47:3576–3585
Johnson RK, McCabe FL, Cauder E et al (2002) SB-715992, a potent and selective inhibitor of the mitotic kinesin KSP, demonstrates broad-spectrum activity in advanced murine tumors and human tumor xenografts. Proc Am Assoc Cancer Res 43:A1335
Rodon J, Till E, Patnaik A et al (2006) Phase I study of ispinesib (SB-715992), a kinesin spindle protein inhibitor, in combination with capecitabine in patients with advanced solid tumors. Eur J Canc Suppl 4:193, Abstr 640
Shahin MS, Braly P, Rose P et al (2007) A phase II, open-label study of ispinesib (SB-715992) in patients with platinum/taxane refractory or resistant relapsed ovarian cancer. J Clin Oncol 25:5562
Heath EI, Alousi A, Eder JP et al (2006) A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day cycle in patients with advanced solid tumors. J Clin Oncol 24:2026
Chu QS, Holen KD, Rowinsky EK et al (2004) Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV Q 21 days. J Clin Oncol 22:2078
Blagden SP, Molife LR, Seebaran A et al (2008) A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours. Br J Cancer 98:894–899
Lee CW, Belanger K, Rao SC et al (2008) A phase II study of ispinesib (SB-715992) in patients with metastatic or recurrent malignant melanoma: a National Cancer Institute of Canada Clinical Trials Group trial. Invest New Drugs 26:249–255
Tang PA, Siu LL, Chen EX et al (2008) Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck. Invest New Drugs 26:257–264
Author information
Authors and Affiliations
Corresponding author
Additional information
Previous study presentations
2004 ASCO Annual Meeting
Rights and permissions
About this article
Cite this article
Burris, H.A., Jones, S.F., Williams, D.D. et al. A phase I study of ispinesib, a kinesin spindle protein inhibitor, administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors. Invest New Drugs 29, 467–472 (2011). https://doi.org/10.1007/s10637-009-9374-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-009-9374-x