title: 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).
abstract: 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.
authors.affiliation: Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, ON, Canada M5G 2M9. jennifer.knox@uhn.on.ca
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Knox
authors.forename: Sharlene
authors.initials: S
authors.lastname: Gill
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
authors.forename: James J
authors.initials: JJ
authors.lastname: Biagi
authors.forename: Pierre
authors.initials: P
authors.lastname: Major
authors.forename: Ron
authors.initials: R
authors.lastname: Feld
authors.forename: Christine
authors.initials: C
authors.lastname: Cripps
authors.forename: Nancy
authors.initials: N
authors.lastname: Wainman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eisenhauer
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D007262:Infusions, Intravenous; D016547:Kinesins / Q000037:antagonists & inhibitors; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C470243:KIF11 protein, human; D011799:Quinazolines; C508757:ispinesib; D016547:Kinesins