Anti-hormone Therapy

344 K. Paz · Z. Zhu
but there were mild–moderate side effects included nausea, diarrhea and
fatigue. Median time on study was 13 weeks (range 2–86 weeks), and no
maximal tolerated dose (MTD) was reached. In a dose-escalation pharmacological
study, SU6668 was administered at 100 or 200 mg/kg to 16 patients
with advanced solid tumors. No significant toxicities were observed. SU6668
was extensively bound to plasma proteins. A three-times daily dose regime
suggested an MTD of 100 mg/kg when administered with food. Half-life was
3.6 h. A dose of 300 mg/kg administered with food was well tolerated among
35 patients, with adverse effects including fatigue and joint pains. DLT was
400 and 800 mg/kg with grade III thrombocytopenia. Four patients had stable
disease for more than 6 months. Phase I data were presented at the 39th
ASCO meeting, June 2003. A group of 24 patients with advanced solid tumors
were given between 200 and 500 mg/kg/day of SU6668 for 28 days. Grade I
and II toxicities were edema, nausea, vomiting, fatigue, anorexia, and abdominal
pain. One patient had grade IV pericardial effusion at the 400 mg
dose. Plasma concentration was lower on day 28 than day 1. Among this
group, ten patients achieved stable disease, but no objective responses were
observed [245, 254]. SUGEN (Pharmacia) initiated a US phase II trial and
a collaborative (Taiho) Japan phase I/II trial for SU6668 in February 2003 and
June 2004, respectively. Data from this trial were presented at the 42nd ASCO
meeting, in June 2006. The study involved 15 patients with hepatocellular carcinoma
(HCC) who were dosed either 400 or 800 mg/day. The higher dose
produced toxicities of grade III abdominal pain and ascites in two patients,
whilethelowerdosedidnotinduceanyadverseevents.Onepatientexhibited
a partial response and another six had stable disease.
Sunitinib (SU11248 or Sutent) [255–258] displays selectivity for members
ofthesplitkinasedomainsubgroup,KDR,PDGFR-alpha,PDGFR-beta,c-
Kit, and Flt3, with in vitro IC50 values in the nanomolar range (14 nM) [185,
259–262]. In biological and cellular assays, Sunitinib competitively inhibited
ligand-dependent KDR and PDGFR-beta autophosphorylation with IC50
values of 10nM [262–265]. In mouse xenograft models, Sunitinib inhibited
the phosphorylation of PDGFR-beta, KDR and c-Kit time- and dosedependently.
Sunitinib demonstrated broad and potent antitumor activity,