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A phase II and pharmacokinetic study of SB-715992, in patients with metastatic hepatocellular carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG IND.168)

  • PHASE II STUDIES
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Summary

Hepatocellular carcinoma (HCC) remains a lethal treatment-resistant cancer with a median survival of <6 months in patients not considered candidates for radical surgical treatments. SB-715992 is a novel cytotoxic agent implicated in the inhibition of mitotic kinesin spindle protein (KSP). Based on evidence from preclinical models and phase I trials, we conducted a phase II trial of SB-715992 in chemo-naïve patients with advanced HCC. A non-randomized, non-blinded multicentre two-stage phase II study was completed examining the efficacy, toxicity, and pharmacokinetics of SB-715992 at 18 mg/m2 IV q 3 weeks, in patients with measurable locally advanced, metastatic or recurrent HCC. The predictive value of KSP in archival tumour was assessed. Fifteen patients with metastatic HCC received a median of 3 cycles of SB-715992. The most common grade 3+ toxicities were granulocytopenia, leukocytopenia, diarrhea and liver transaminase rise. Overall confirmed response rate was 0%. Seven (46%) patients had a best response of stable disease at the 8-week evaluation (median duration 3.9 months) Median time to progression was 1.61 months (95%CI = 1.31–3.94 months) SB-715992 plasma concentrations were comparable to those observed in the phase I studies. Expression of KSP by immunohistochemistry was observed in only four of eight evaluable samples with strong expression reported in only two. No correlation was observed between intensity of KSP staining and clinical outcome. Among these patients with preserved hepatic function and good performance status, SB-715992 was generally well tolerated. However, no conclusive evidence of benefit was seen with SB-715992 monotherapy in HCC.

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Acknowledgement

The National Cancer Institute of Canada Clinical Trials Group supported the design, conduct, evaluation and manuscript preparation of this trial; drug was supplied by the National Cancer Institute Division of Cancer Therapy Evaluation Program (CTEP).

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Authors and Affiliations

  1. Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, ON, Canada, M5G 2M9

    Jennifer J. Knox & Ron Feld

  2. British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada, V5Z 4E6

    Sharlene Gill

  3. City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA

    Timothy W. Synold

  4. Department of Oncology, Queen’s University, 25 King Street West, Kingston, ON, Canada, K7L 5P9

    James J. Biagi

  5. Hamilton Regional Cancer Centre, 699 Concession Street, Hamilton, ON, Canada, L8V 5C2

    Pierre Major

  6. The Ottawa Hospital Regional Cancer Centre, 503 Smyth Road, Ottawa, ON, Canada, K1H 1C4

    Christine Cripps

  7. NCI-Canada Clinical Trials Group, Queens University, 10 Stuart Street, Kingston, ON, Canada, K7L3N6

    Nancy Wainman, Elizabeth Eisenhauer & Lesley Seymour

Authors
  1. Jennifer J. Knox
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  2. Sharlene Gill
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  3. Timothy W. Synold
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  4. James J. Biagi
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  5. Pierre Major
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  6. Ron Feld
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  7. Christine Cripps
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  8. Nancy Wainman
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  9. Elizabeth Eisenhauer
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  10. Lesley Seymour
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Corresponding author

Correspondence to Jennifer J. Knox.

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Knox and Sharlene are co-principal investigators.

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Knox, J.J., Gill, S., Synold, T.W. et al. A phase II and pharmacokinetic study of SB-715992, in patients with metastatic hepatocellular carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG IND.168). Invest New Drugs 26, 265–272 (2008). https://doi.org/10.1007/s10637-007-9103-2

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  • DOI: https://doi.org/10.1007/s10637-007-9103-2

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