Investigational New Drugs

, Volume 30, Issue 3, pp 1088–1095 | Cite as

A phase I trial of MK-0731, a Kinesin Spindle Protein (KSP) inhibitor, in patients with solid tumors

  • Kyle Holen
  • Robert DiPaola
  • Glenn Liu
  • Antoinette R. Tan
  • George Wilding
  • Karl Hsu
  • Nancy Agrawal
  • Cong Chen
  • Lingling Xue
  • Elizabeth Rosenberg
  • Mark Stein
PHASE I STUDIES

Summary

Purpose The kinesin spindle protein (KSP) is essential for separation of spindle poles during mitosis. Its inhibition results in mitotic arrest. This phase I trial examined safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic parameters, and anti-tumor activity of MK-0731, a potent inhibitor of KSP. Experimental design In part 1, patients with advanced solid tumors received MK-0731 intravenously over 24 h every 21 days starting at 6 mg/m2, escalating until MTD was reached. In part 2, patients with taxane-resistant tumors received the MTD. Plasma samples were collected to analyze the pharmacokinetics of MK-0731. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Results In part 1, 21 patients (median age 63 years) were treated with MK-0731 at doses ranging from 6 to 48 mg/m2/24 h for median four cycles. The dose-limiting toxicity was neutropenia and the MTD was 17 mg/m2/24 h. At the MTD, AUC (±SD) was 10.5 (±7.3) μM × hour, clearance (±SD) was 153 mL/min (±84), and t1/2 was 5.9 h. In part 2, 22 patients received the MTD and there were no DLTs. Although there were no objective tumor responses, four patients (with cervical, non-small cell lung, and ovarian cancers) had prolonged stable disease. Conclusions MK-0731 at the MTD of 17 mg/m2/day every 21 days in patients with solid tumors had few grade 3 and 4 toxicities with the major DLTs at higher doses being myelosuppression. Anti-tumor efficacy was suggested by the length of stable disease in selected patients with taxane-resistant tumors.

Keywords

Kinesin spindle protein Oncology Neutropenia 

References

  1. 1.
    Morris PG, Fornier MN (2008) Microtubule active agents: beyond the taxane frontier. Clin Cancer Res 14:7167–7172PubMedCrossRefGoogle Scholar
  2. 2.
    Pellegrini F, Budman DR (2005) Review tubulin function, action of antitubulin drugs, and new drug development. Cancer Investig 23:264–273CrossRefGoogle Scholar
  3. 3.
    Risinger AL, Giles FJ, Mooberry SL (2009) Microtubule dynamics as a target in oncology. Cancer Treat Rev 35:255–261PubMedCrossRefGoogle Scholar
  4. 4.
    Hagiwara H, Sunada Y (2004) Mechanism of taxane neurotoxicity. Breast Cancer 11:82–85PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang Y, Xu W (2008) Progress on kinesin spindle protein inhibitors as anti-cancer agents. Anticancer Agents Med Chem 8:698–704PubMedGoogle Scholar
  6. 6.
    Sakowicz R, Finer JT, Beraud C, Crompton A, Lewis E, Fritsch A, Lee Y, Mak J, Moody R, Turincio R, Chabala JC, Gonzales P, Roth S, Weitman S, Wood KW (2004) Antitumor activity of a kinesin inhibitor. Cancer Res 64:3276–3280PubMedCrossRefGoogle Scholar
  7. 7.
    Blagden SP, Molife LR, Seebaran A, Payne M, Reid AH, Protheroe AS, Vasist LS, Williams DD, Bowen C, Kathman SJ, Hodge JP, Dar MM, de Bono JS, Middleton MR (2008) A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours. Br J Cancer 98:894–899PubMedCrossRefGoogle Scholar
  8. 8.
    Beer TM, Goldman B, Synold TW, Ryan CW, Vasist LS, Van VP Jr, Dakhil SR, Lara PN Jr, Drelichman A, Hussain MH, Crawford ED (2008) Southwest Oncology Group phase II study of ispinesib in androgen-independent prostate cancer previously treated with taxanes. Clin Genitourin Cancer 6:103–109PubMedCrossRefGoogle Scholar
  9. 9.
    Lee CW, Belanger K, Rao SC, Petrella TM, Tozer RG, Wood L, Savage KJ, Eisenhauer EA, Synold TW, Wainman N, Seymour L (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 26:249–255PubMedCrossRefGoogle Scholar
  10. 10.
    Carol H, Lock R, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Reynolds CP, Maris JM, Keir ST, Billups CA, Smith MA (2009) Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program. Pediatr Blood CancerGoogle Scholar
  11. 11.
    Holen KD, Hodge JP, Dar MM, Ho PT (2010) A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharamcokinetics, biologic effecs, and establish a recommended phase II dose. Cancer Chemother Pharmacol [Epub ahead of print]Google Scholar
  12. 12.
    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 150:975–988PubMedCrossRefGoogle Scholar
  13. 13.
    Tao W, South VJ, Zhang Y, Davide JP, Farrell L, Kohl NE, Sepp-Lorenzino L, Lobell RB (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 8:49–59PubMedCrossRefGoogle Scholar
  14. 14.
    Tao W, South VJ, Diehl RE, Davide JP, Sepp-Lorenzino L, Fraley ME, Arrington KL, Lobell RB (2007) An inhibitor of the kinesin spindle protein activates the intrinsic apoptotic pathway independently of p53 and de novo protein synthesis. Mol Cell Biol 27:689–698PubMedCrossRefGoogle Scholar
  15. 15.
    Data available at Merck & Co., Inc. West Point, PAGoogle Scholar
  16. 16.
    Cox CD, Coleman PJ, Breslin MJ, Whitman DB, Garbaccio RM, Fraley ME, Buser CA, Walsh ES, Hamilton K, Schaber MD, Lobell RB, Tao W, Davide JP, Diehl RE, Abrams MT, South VJ, Huber HE, Torrent M, Prueksaritanont T, Li C, Slaughter DE, Mahan E, Fernandez-Metzler C, Yan Y, Kuo LC, Kohl NE, Hartman GD (2008) Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-n-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2- (hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer. J Med Chem 51:4239–4252PubMedCrossRefGoogle Scholar
  17. 17.
    Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC (1997) Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89:1138–1147PubMedCrossRefGoogle Scholar
  18. 18.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  19. 19.
    Heath EI, Alousi JP, Eder M, Valdivieso LS, Vasist L, Appleman P, Bhargava AD, Colevas PM, Lorusso PM, Shapiro G (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, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 24, No 18S (June 20 Supplement): 2026Google Scholar
  20. 20.
    Chu QS, Holen KD, Rowinsky EK, Wilding G, Volkman JL, Orr JB, Williams DD, Hodge JPSJ (2004) Phase I trial of a novel kinesin spindle protein (KSP) inhibitor SB715992 IV Q 21 days. J Clin Oncol, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement): 2078Google Scholar
  21. 21.
    Burris HA, Lorusso P, Jones S, Guthrie TM, Orr JB, Williams DD, Hodge JP, Bush M, Sabry J (2004) Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV days 1, 8, 15 q28 days. J Clin Oncol, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement): 2004Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Kyle Holen
    • 1
  • Robert DiPaola
    • 2
  • Glenn Liu
    • 1
  • Antoinette R. Tan
    • 2
  • George Wilding
    • 1
  • Karl Hsu
    • 3
  • Nancy Agrawal
    • 3
  • Cong Chen
    • 3
  • Lingling Xue
    • 3
  • Elizabeth Rosenberg
    • 3
  • Mark Stein
    • 2
  1. 1.University of Wisconsin Carbone Cancer CenterMadisonUSA
  2. 2.Cancer Institute of New JerseyNew BrunswickUSA
  3. 3.MerckWhitehouse StationUSA

Personalised recommendations