UNASSIGNED: 2600 Background: @entity68991 is an allosteric inhibitor of @entity13501 which selectively inhibits bipolar mitotic spindle formation. The objective of this Phase 1 study is to determine the Phase 2 dose and schedule of @entity68991 that can be safely administered to @entity1 with advanced @entity5 . METHODS: Study I1Y-MC-JFBB is an open-label, dose-escalation study in @entity1 with advanced @entity5 . The study consists of a 3+3 dose escalation phase followed by a dose confirmation phase. Eligible @entity1 receive @entity68991 as a 1 hr infusion on either Days 1, 5, and 9; Days 1, and 8; or Days 1, and 5 with peg on Day 6; of a 21-day cycle. Due to the multiple doses per cycle schedule, the traditional maximum tolerated dose (MTD) definition was conservatively modified to include dose omissions (DO) and dose reductions (DR) in addition to standard dose limiting @entity137 (DLT). @entity1 were assessed every 2 cycles per RECIST criteria. IHC expression of pHH3, Ki-67, and @entity13501 was quantified in serial skin biopsies. RESULTS: 46 @entity1 have been enrolled in the study as of October 2010. The most frequent AEs (>= 10%) reported include @entity1398 , @entity1295 , @entity390 , @entity391 , @entity1910 and @entity448 . @entity137 qualifying as DLT or DR/DO were @entity1398 or @entity1398 . To date, 16 @entity1 have had stable disease for greater than 2 cycles. Single and multiple dose pharmacokinetics (PK) of @entity68991 and metabolite were characterized. @entity68991 clearance was dose-independent and exposure increased in a dose-dependent manner. There was negligible intra- and inter-cycle accumulation of @entity68991 . Several PK and other parameters were examined for correlation with DR/DO/DLT for the Days 1, 5 and 9 and the Days 1 and 8 schedules but none were identified as significant. @entity13501 inhibitor treatment-related dose and exposure dependent changes in pHH3, and @entity13501 expression in skin have been demonstrated. CONCLUSIONS: Recently, the MTD for the Days 1, 5 and 9; and Days 1 and 8 schedules has been established at 8 mg/m(2)/d. This dose has shown a @entity1726 response in surrogate skin biopsies for both schedules. Dose escalation and expansion on the Days 1, and 5 plus peg is on-going.

A phase I dose-escalation study of XXXX , an @entity13501 inhibitor, administered either on days 1, 5, and 9; days 1 and 8; or days 1 and 5 with pegfilgrastim (peg) every 21 days (NCT01214642).

@entity1 :: ('9606', 'Species') :: ['Patients', 'patients'] @entity137 :: ('MESH:D064420', 'Disease') :: ['Toxicities', 'toxicities'] @entity390 :: ('MESH:D009325', 'Disease') :: ['nausea'] @entity1910 :: ('MESH:D005076', 'Disease') :: ['rash'] @entity5 :: ('MESH:D009369', 'Disease') :: ['malignancy', 'malignancies'] @entity391 :: ('MESH:D014839', 'Disease') :: ['vomiting'] @entity1295 :: ('MESH:D005221', 'Disease') :: ['fatigue'] @entity448 :: ('MESH:D000855', 'Disease') :: ['anorexia'] @entity1726 :: ('OMIM:168600', 'Disease') :: ['PD'] @entity1398 :: ('MESH:D009503', 'Disease') :: ['neutropenia', 'febrile neutropenia'] @entity68991 :: ('MESH:C000591843', 'Chemical') :: ['LY2523355'] @entity13501 :: ('3832', 'Gene') :: ['Eg5']
@entity68991 :: (MESH:C000591843,Chemical) :: ['LY2523355']
