[2001]-[XR9576]-[P-Glycoprotein Inhibitor][A Phase IIA Pharmacokinetic Study of the P-Glycoprotein Inhibitor, XR9576 in Combination with Paclitaxel in Patients with Ovarian Cancer.]
Publication Year: 2001
A Phase IIA Pharmacokinetic Study of the P-Glycoprotein Inhibitor, XR9576 in Combination with Paclitaxel in Patients with Ovarian Cancer.
Hilary Thomas, Janice A Steiner, Graham P Mould, Graham Mellows, Alistair J Stewart, David B Norris, John F Waterfall, Royal Surrey County Hospital, Guildford, UK; Xenova Limited, Slough, UK; Guildford Clinical Pharmacology, Guildford, UK.
XR9576 has been shown to reverse P-gp-dependent MDR in vitro and in vivo (Mistry et al , Proc. Amer. Cancer Res. 1999, 40, p313). Phase I data in volunteers showed the compound to be well tolerated. The aim of this open label study was to evaluate the pharmacokinetic and pharmacodynamic interactions of 150mg fixed single dose of XR9576, 175mg/m[sup2] paclitaxel and the combination of the two, given in that order. XR9576 was given as a 30 min infusion on days 1 and 29. Paclitaxel was given as a 3 hr infusion on days 8 and 29, starting 1.5 hrs after the end of the XR9576 infusion. Patients could then receive up to a further 4 cycles of XR9576 and paclitaxel at three weekly intervals in combination with carboplatin. Twelve patients with ovarian cancer recurring more than six months after treatment with paclitaxel or second or third line after any other chemotherapy were recruited over a seven month period. Two patients had received prior paclitaxel and all twelve patients had received previous platinum-containing regimens. Eleven patients were treated second line and one as third line chemotherapy. 150mg of XR9576 given in combination with 175mg/m[sup2] of paclitaxel did not alter the plasma profile of paclitaxel to any clinically significant extent. There was no evidence of toxicity in excess of what would be expected in this population treated with paclitaxel and carboplatin alone. Eleven patients had measurable and one patient assessable disease. Two patients developed progressive disease within the first 2 cycles, a further two within four cycles of treatment. Seven remaining patients completed six cycles of treatment and one received eight cycles. Two patients obtained a complete remission of six and ten months post treatment (latter ongoing) respectively. Two patients obtained a partial remission, three had disease stabilisation. The patient with assessable disease had complete resolution of her ascites. Ten out of the twelve patients had a fall in CA125 of which three had a partial and three a complete biochemical remission. This level of activity is encouraging and warrants further investigation of this agent.
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