PURPOSE: @entity55760 ( @entity55760 , Incel) restores drug sensitivity to cells expressing @entity1262 ( @entity70395 ). @entity11092 is expressed in a high proportion of @entity263 while @entity1262 expression is variable. Since @entity2664 (M) and @entity229 (P) are substrates for MDR transporters, we initiated a study to evaluate the safety, pharmacokinetics, and efficacy of @entity55760 plus M/P in @entity1 with @entity263 ( @entity263 ). @entity1 AND METHODS: Eligible @entity1 had progressive @entity263 (defined as new lesions, new disease-related @entity158 , or 50% increase in PSA within 6 weeks of entry), @entity251 <30 ng/ml, no prior chemotherapy, ECOG performance status of 0-3, and adequate organ function. @entity1 received @entity55760 (120 mg/m(2) per h) as a 72-h continuous intravenous infusion with intravenous bolus @entity2664 (12 mg/m(2)) administered 4 h after @entity55760 was started and @entity229 (5 mg twice daily) administered throughout the study treatment. Endpoints included serum PSA response, PSA response duration, time to PSA progression, @entity158 reduction, and quality of life measures. RESULTS: Enrolled in the study were 40 @entity1 and 184 courses of @entity55760 plus M/P were administered. Intensive pharmacokinetics, which were performed on six @entity1 who received one cycle of M/P alone, followed by @entity55760 plus M/P for all other cycles, showed that @entity55760 did not alter @entity2664 clearance. @entity55760 blood concentration at the time of @entity2664 administration averaged 4.52 microg/ml. @entity55760 plus M/P was well tolerated. @entity1209 and mild @entity1398 were the principal treatment @entity137 . Five @entity1 experienced an uncomplicated febrile neutropenic episode (12%), three had severe @entity390 / @entity391 , and two experienced transient moderate to severe @entity2055 . Of the 40 @entity1 , 12 (30%, 95% confidence interval 16-44%) had a reduction in PSA of >/=50% and 9 of the 12 @entity1 (23% overall, 95% CI 10-35%) achieved a reduction in PSA of >/=80% that was sustained for the duration of treatment with M/P plus @entity55760 . The median time to PSA progression was 41 weeks (95% CI 34-68 weeks). Of the 40 @entity1 , 15 completed treatment with stable disease and 13 had progressive disease with increasing serum PSA during study treatment. Median survival was 48 weeks for the intent-to-treat population of 40 @entity1 . CONCLUSIONS: The addition of @entity55760 to M/P therapy did not appear to increase the proportion of @entity1 with significant serum PSA reductions compared to M/P alone. However, the duration of PSA response observed for the 12 PSA responders suggests that MDR inhibition may benefit some @entity1 with @entity263 . In addition to @entity11092 or @entity1262 expression, other mechanisms of drug resistance are probably associated with the relative insensitivity of @entity263 to cytotoxic therapy.

Safety and efficacy of the MDR inhibitor Incel (biricodar, @entity55760 ) in combination with @entity2664 and @entity229 in XXXX .

@entity1 :: ('9606', 'Species') :: ['Patients', 'patients', 'PATIENTS'] @entity1262 :: ('5243', 'Gene') :: ['P-glycoprotein', 'P-gp'] @entity251 :: ('MESH:D013739', 'Chemical') :: ['testosterone'] @entity263 :: ('MESH:D011471', 'Disease') :: ['prostate tumors', 'hormone-refractory prostate cancer', 'HRPC'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicities'] @entity390 :: ('MESH:D009325', 'Disease') :: ['nausea'] @entity229 :: ('MESH:D011241', 'Chemical') :: ['prednisone'] @entity2664 :: ('MESH:D008942', 'Chemical') :: ['mitoxantrone'] @entity391 :: ('MESH:D014839', 'Disease') :: ['vomiting'] @entity1398 :: ('MESH:D009503', 'Disease') :: ['neutropenia'] @entity11092 :: ('4363', 'Gene') :: ['MRP1'] @entity70395 :: ('283871;8714', 'Gene') :: ['P-gp) and multidrug resistance-associated protein (MRP1'] @entity158 :: ('MESH:D010146', 'Disease') :: ['pain'] @entity55760 :: ('MESH:C106077', 'Chemical') :: ['biricodar', 'VX-710'] @entity2055 :: ('MESH:D001259', 'Disease') :: ['ataxia'] @entity1209 :: ('MESH:D020250', 'Disease') :: ['Transient nausea/vomiting']
@entity263 :: (MESH:D011471,Disease) :: ['hormone-refractory prostate cancer']
