UNASSIGNED: 2040 Background: @entity68820 is a novel @entity3907 that has demonstrated exceptional activity in @entity1 xenograft models when administered intravenously and orally. Preclinical studies of @entity68820 have shown antitumor activity in MDR-expressing and @entity1311 -resistant @entity5 . METHODS: This phase 1 ascending-dose study was performed to determine the safety and tolerability of orally administered @entity68820 given once every 21 days. Preliminary antitumor activity of @entity68820 was also examined. Key eligibility criteria included adult @entity1 with refractory solid @entity5 , good performance status (ECOG <=  2), and adequate hematologic, hepatic, and renal function. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. RESULTS: 18 @entity1 (4 females, 14 males) were evaluated at 5 dose levels ranging from 25 to 75 mg/m(2). Treatment was well tolerated at the first 3 dose levels (25, 37, 50 mg/m(2)). Two @entity1 developed dose-limiting @entity137 (DLTs) at 75 mg/m(2) (1 @entity1 with grade 3 @entity1398 with @entity221 , another @entity1 had grade 4 @entity1398 with @entity221 ). Three @entity1 were treated at an intermediate dose level of 60 mg/m(2) without DLTs. Other common @entity137 included grade 1-2 fatigue and grade 1-2 @entity294 . Disease stabilization was seen in 4 @entity1 with the following @entity5 : mesothelioma (14 cycles), @entity511 (12 cycles), @entity4153 (10 cycles), and @entity263 (6 cycles). There was substantial interpatient variability in the PK parameters. @entity68820 was absorbed rapidly with mean Tmax less than 1 hour. Mean Cmax and AUC values generally increased in a dose-related manner. The elimination half-life ranged from 20-228 hours. CONCLUSIONS: @entity68820 can be safely administered orally once every 21 days up to a dose of 60 mg/m(2). The major DLT was @entity221 . Four @entity1 had disease stabilization. This study is ongoing to confirm 60 mg/m(2) as the maximum tolerated dose and to determine the oral bioavailability of @entity68820 . [Table: see text].

Phase 1 trial of oral @entity68820 in subjects with advanced XXXX .

@entity1 :: ('9606', 'Species') :: ['human', 'patients', 'patient'] @entity68820 :: ('MESH:C479501', 'Chemical') :: ['MAC-321'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicities'] @entity511 :: ('MESH:D002813', 'Disease') :: ['chondrosarcoma'] @entity4153 :: ('MESH:D018288', 'Disease') :: ['small cell carcinoma'] @entity263 :: ('MESH:D011471', 'Disease') :: ['prostate carcinoma'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumors'] @entity294 :: ('MESH:D003967', 'Disease') :: ['diarrhea'] @entity1311 :: ('MESH:D017239', 'Chemical') :: ['paclitaxel'] @entity3907 :: ('MESH:C080625', 'Chemical') :: ['taxane'] @entity1398 :: ('MESH:D009503', 'Disease') :: ['neutropenia'] @entity221 :: ('MESH:D005334', 'Disease') :: ['neutropenic fever', 'fever']
@entity5 :: (MESH:D009369,Disease) :: ['malignant solid tumors']
