[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.]
[Proceedings of the 11th NCI · EORTC · AACR Symposium]
Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy
Published by the AACR.
191 A phase IIA pharmacokinetic study of the P-glycoprotein inhibitor, XR9576, in combination with paclitaxel in patients with ovarian cancer.
Thomas Hilary, Steiner Janice, Mould Graham, Mellows Graham, Stewart Alistair, Norris David, Waterfall John. Xenova Limited, 240 Bath Road, Slough, Berks SL1 4EF UK.
XR9576 is a novel selective and potent modulator of P-glycoprotein dependent multidrug resistance and was well tolerated in Phase I healthy volunteer studies (Steiner et al, Clinical Cancer Research 5 (Suppl), 3832s, 1999). A Phase IIA clinical trial in twelve patients was undertaken to evaluate whether there is any pharmacokinetic or pharmacodynamic interaction between XR9576 and paclitaxel in patients with ovarian cancer recurring more than six months after previous treatment. XR9576 (150mg) was given as a single intravenous infusion over 30 minutes on Day 1, and paclitaxel (175mg/m2) as a single 3-hour infusion on Day 8. On Day 29 XR9576 was given 2 hours prior to paclitaxel. Blood samples were taken for measurement of XR9576, paclitaxel and a surrogate marker of efficacy at various time-points for up to 168 hours. Following the first cycle of treatment patients were treated with up to six additional cycles, at three-weekly intervals, in conjunction with carboplatin.
Pre-treatment with XR9576, had no marked effect on the mean pharmacokinetic parameters of paclitaxel. The results indicate it is safe to administer XR9576 with full doses of paclitaxel, in contrast to other P-gp inhibitors.
Col Headings:
Paclitaxel Alone(CV%)
Paclitaxel+XR9576(CV%)
XR9576 Alone(CV%)
XR9576 + Paclitaxel(CV%)
PK Parameter
AUC(0-) 14987 (23.0) 17955(49.4) 11887(43.8) 19753(33.3)
t1/2(h) 20.3 (21.5) 17.2 (27.8) 33.9 (40.6) 27.1 (20.5)
CL(L/h/m2)11.7(23.6) 9.8 (48.8) 7.19 (47.5) 4.36 (34.1)
Vss(L/m2) 82.1(18.3) 58.3(88.4) 293 (29.1) 155 (16.5)
Four of the twelve patients were withdrawn due to disease progression and eight completed the courses of treatment.
CT scans were taken prior to entry, after cycles 2 and 4 and at follow-up. CA125 levels were assayed prior to each cycle of treatment. Results of the CT scans, the CA125 concentrations and safety data will be presented.
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