[2001]-[XR9576]-[P-Glycoprotein Inhibitor][Phase 1 Study]
Publication Year: 2001
Visited: 342
A Phase I Study of the Novel P-Glycoprotein (Pgp) Antagonist, XR9576 in Combination with Vinorelbine.
Jame Abraham, Maureen Edgerly, Richard Wilson, Clara Chen, Wilma Medina, Leslyn Hermonstine, Ann Rutt, Susan Bakke, Robert Robey, Andrew Dwyer, Barry Goldspiel, Jan Steiner, David Norris, Jean Grem, A Guemei, Susan Bates, Tito Fojo, NCI/NIH, Bethesda, MD; Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD; Department of radiology, National Institutes of Health, Bethesda, MD; Department of Pharmacy, Clinical Center, NIH, Bethesda, MD; Xenova Ltd., Slough, Berkshire, UK.
Drug resistance is a major cause of chemotherapy failure. Clinical trials investigating Pgp antagonists have been hampered by unpredictable pharmacokinetic (PK) interactions, requiring reductions of chemotherapeutic doses to avert excessive toxicity. XR9576 is a novel, potent Pgp antagonist. We conducted a phase I study to determine the safety of XR9576 in combination with vinorelbine and determine the extent, if any, of a pharmacokinetic interaction. Tc-99m Sestamibi scans and measurements of rhodamine efflux from CD56+ cells were performed in all patients. Seventeen patients have been enrolled; 14 are evaluable (4M/10F). Median age is 50.5 yrs; performance status ECOG 0 - 2. Median number of prior chemotherapy agents is 5.2. Patients receive 150 mg XR-9576 iv on days 1 and 8 prior to vinorelbine. Starting dose of vinorelbine was 15 mg/m2 on days 1 and 8. 20 mg/m2 has been tolerated; accrual to 22.5 mg/m2 is planned. Total number of cycles administered is 54, median 3.8. Episodes of grade 3 toxicities in 54 cycles include: abdominal pain (3), myalgia (2), fatigue (2), and diarrhea, constipation vomiting, anorexia, depression, neutropenia and ileus (all once). One patient each with breast cancer and renal cancer responded to therapy. A single dose of XR9576 reduced liver clearance of Tc-99m Sestamibi in all patients (consistent with inhibition of Pgp-mediated liver excretion), and increased retention in some patients tumors, and blocked Pgp-mediated rhodamine efflux from circulating CD56+ cells in all patients over the 48 hours. Administration of XR9576 resulted in a 15% increase in AUC, and reduced clearance of vinorelbine which were not statistically significant. In summary XR9576 is a potent Pgp antagonist, active in vivo, without significant side effects and much less PK interaction than first and second generation Pgp antagonists.
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