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Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck

  • PHASE II STUDIES
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Summary

Ispinesib (SB-715992) inhibits the mitotic kinesin spindle protein (KSP), a novel target for anticancer therapy. A phase II study was conducted to examine the efficacy of ispinesib in recurrent or metastatic head and neck squamous cell carcinoma (RMHNSC). Patients with up to one prior line of chemotherapy for RMHNSC were treated with ispinesib 18 mg/m2 IV over 1 hour every 21 days. Twenty-one patients were enrolled onto this study with a target stage I sample size of 19. Of 20 evaluable patients, no objective responses were seen and stable disease > 2 cycles was observed in five patients (25%). The median time to progression was 1.4 (95% CI 1.3–2.3) months, median survival was 3.5 (95% CI 2.8–7.8) months, and 1 year overall survival was 20% (95% CI 8.3–48.1%). The most frequent attributable grades III–V adverse events were neutropenia (60% of patients) and leukopenia (55%). The pharmacokinetic profile was consistent with results from phase I studies. Archival tissues (n = 14) demonstrated low to moderate KSP expression by immunohistochemistry. In addition, no pharmacodynamic changes were observed in peripheral blood mononuclear cells. We detected no antitumor activity of ispinesib in RMHNSC on this dosing schedule.

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References

  1. A phase III randomised trial of cisplatinum, methotrextate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck (1990) Liverpool Head and Neck Oncology Group. Br J Cancer 61:311–315

  2. Clavel M, Vermorken JB, Cognetti F, Cappelaere P, de Mulder PH, Schornagel JH, Tueni EA, Verweij J, Wildiers J, Clerico M, Dalesio O, Kirkpatrick A, Snow GB (1994) Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 5:521–526

    PubMed  CAS  Google Scholar 

  3. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK, Von Hoff DD (1992) Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 10:1245–1251

    PubMed  CAS  Google Scholar 

  4. Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J, Forastiere AA (2005) Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 23:3562–3567

    Article  PubMed  CAS  Google Scholar 

  5. Williams SD, Velez-Garcia E, Essessee I, Ratkin G, Birch R, Einhorn LH (1986) Chemotherapy for head and neck cancer. Comparison of cisplatin + vinblastine + bleomycin versus methotrexate. Cancer 57:18–23

    Article  PubMed  CAS  Google Scholar 

  6. Jacobs C, Lyman G, Velez-Garcia E, Sridhar KS, Knight W, Hochster H, Goodnough LT, Mortimer JE, Einhorn LH, Schacter L, Cherng N, Dalton T, Burroughs J, Rozencweig M (1992) A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10:257–263

    PubMed  CAS  Google Scholar 

  7. Wood KW, Cornwell WD, Jackson JR (2001) Past and future of the mitotic spindle as an oncology target. Curr Opin Pharmacol 1:370–377

    Article  PubMed  CAS  Google Scholar 

  8. Vale RD, Milligan RA (2000) The way things move: looking under the hood of molecular motor proteins. Science 288:88–95

    Article  PubMed  CAS  Google Scholar 

  9. Mak J, Freedman R, Beraud C (2002) Utilization of gene expression profiles to identify mitotic kinesins (Abstract). Annu Meet Am Assoc Cancer Res Proc 43:A5375

    Google Scholar 

  10. 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 64:3276–3280

    Article  PubMed  CAS  Google Scholar 

  11. Johnson RK, McCabe FL, Caulder E, Innlow L, Whitacre M, Winkler JD, Bergnes G, Feng B, Smith WW, Morgans D, Wood K, Jackson JR (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 (Abstract). Annu Meet Am Assoc Cancer Res Proc 43:A1355

    Google Scholar 

  12. 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 q 28 days. J Clin Oncol (Meeting Abstracts) 22:2004

    Google Scholar 

  13. Chu QS, Holen KD, Rowinsky EK, Wilding G, Volkman JL, Orr JB, Williams DD, Hodge JP, Kerfoot CA, Sabry J (2004) Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV Q 21 days. J Clin Oncol (Meeting Abstracts) 22:2078

    Google Scholar 

  14. Heath EI, Alousi A, Eder JP, Valdivieso M, Vasist LS, Appleman L, Bhargava P, Colevas AD, 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 (Meeting Abstracts) 24:2026

    Google Scholar 

  15. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubenstein 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 92:205–216

    Article  PubMed  CAS  Google Scholar 

  16. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10

    Article  PubMed  CAS  Google Scholar 

  17. Saijo T, Ishii G, Ochiai A, Yoh K, Goto K, Nagai K, Kato H, Nishiwaki Y, Saijo N (2006) Eg5 expression is closely correlated with response of advanced non-small cell lung cancer to antimitotic agents combined with platinum chemotherapy. Lung Cancer 54:217–225

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NCI contract number N01-CM-62203, and Translational Research Initiative contract number 24XS146.

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Authors and Affiliations

  1. Princess Margaret Phase II Consortium, Toronto, ON, Canada

    Patricia A. Tang, Lillian L. Siu, Eric X. Chen, Sebastien J. Hotte, Stephen Chia, James K. Schwarz, Gregory R. Pond, Caitlin Johnson & Eric Winquist

  2. Division of Oncology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA

    A. Dimitrios Colevas

  3. Division of Medical Oncology, Department of Clinical and Molecular Pharmacology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Timothy W. Synold

  4. Department of Clinical Pharmacokinetics/Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC, USA

    Lakshmi S. Vasist

  5. London Health Sciences Centre, 790 Commissioners Road East, London, ON, Canada, N6A 4L6

    Eric Winquist

Authors
  1. Patricia A. Tang
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  2. Lillian L. Siu
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  3. Eric X. Chen
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  4. Sebastien J. Hotte
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  5. Stephen Chia
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  6. James K. Schwarz
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  7. Gregory R. Pond
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  8. Caitlin Johnson
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  9. A. Dimitrios Colevas
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  10. Timothy W. Synold
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  11. Lakshmi S. Vasist
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  12. Eric Winquist
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Corresponding author

Correspondence to Eric Winquist.

Appendix 1

Appendix 1

Pharmacokinetic Analysis

Blood samples were centrifuged at 2500 × g for 10 minutes at 5°C. Plasma samples were stored in a polypropylene storage tube at −20°C until shipment. The high performance liquid chromatography-mass spectrometry/ mass spectrometry method used in this study has been validated over the range 0.1 to 100 ng/mL. Ispinesib was extracted from 50 μL of human plasma by protein precipitation using 75/25 acetonitrile/10 mM ammonium formate (pH 3) containing an isotopically labeled internal standard ([2H4]-SB-715992). Extracts were analyzed by HPLC-MS/MS using a TurboIonSpray™ interface and multiple reaction monitoring.

Molecular Correlates

Primary antibodies:

Sigma T4026: Monoclonal Anti-β-Tubulin antibody produced in mouse

Sigma H9908: Monoclonal Anti-phospho-Histone H3 (pSer28) antibody produced in rat

Secondary antibodies:

Sigma F2883: Anti-Mouse IgG (whole molecule) F(ab′)2 fragment–FITC antibody produced in sheep

Biomeda R06: Anti-Rat IgG (Mouse Ads.)- Rhodamine antibody produced in goat

Nuclear stain:

Sigma D9542: 4′,6-Diamidino-2-phenylindole dihydrochloride (DAPI)

The slides were mounted with Vector H-1400: VECTASHIELD HardSet Mounting Medium

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Tang, P.A., Siu, L.L., Chen, E.X. et al. Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck. Invest New Drugs 26, 257–264 (2008). https://doi.org/10.1007/s10637-007-9098-8

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  • DOI: https://doi.org/10.1007/s10637-007-9098-8

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