BACKGROUND: Aberrant Notch activation confers a proliferative advantage to many @entity1 @entity5 , including @entity320 . This phase 2 trial assessed the antitumor activity of @entity1134 , a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of @entity1 with advanced @entity320 . METHODS: Chemotherapy-naive @entity1 with @entity320 of cutaneous or unknown origin were treated orally with @entity1134 at a dose of 20 mg daily 3 consecutive days per week. A 2-step accrual design was used with an interim analysis of the first 32 @entity1 and with continuation of enrollment if 4 or more of the 32 @entity1 responded. RESULTS: Thirty-six @entity1 from 23 institutions were enrolled; 32 @entity1 were evaluable. @entity1134 was well tolerated, and most @entity137 were grade 1 or 2. The most common @entity137 were @entity390 (53%), @entity1295 (41%), and @entity417 (22%). There was 1 confirmed partial response lasting 7 months, and there were 8 @entity1 with stable disease lasting at least through week 12, with 1 of these continuing for 31 months. The 6-month progression-free survival rate was 9% (95% confidence interval [CI], 2%-22%), and the 1-year overall survival rate was 50% (95% CI, 32%-66%). Peripheral blood T-cell assays showed no significant inhibition of the production of @entity1199 , a surrogate pharmacodynamic marker of Notch inhibition, and this suggested that the drug levels were insufficient to achieve Notch target inhibition. CONCLUSIONS: @entity1134 showed minimal clinical activity against @entity320 in this phase 2 trial, possibly because of inadequate exposure to therapeutic drug levels. Although Notch inhibition remains a compelling target in @entity320 , the results do not support further investigation of @entity1134 with this dose and schedule. @entity5 2014.    2014 American @entity5 Society.

Phase 2 study of @entity1134 , a gamma-secretase inhibitor, in XXXX : SWOG 0933.

@entity1 :: ('9606', 'Species') :: ['human', 'patients'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicities'] @entity390 :: ('MESH:D009325', 'Disease') :: ['nausea'] @entity417 :: ('MESH:D000740', 'Disease') :: ['anemia'] @entity5 :: ('MESH:D009369', 'Disease') :: ['Cancer', 'tumors'] @entity1295 :: ('MESH:D005221', 'Disease') :: ['fatigue'] @entity1134 :: ('MESH:C545185', 'Chemical') :: ['RO4929097'] @entity1199 :: ('3558', 'Gene') :: ['interleukin-2'] @entity320 :: ('MESH:D008545', 'Disease') :: ['melanoma', 'metastatic melanoma']
@entity320 :: (MESH:D008545,Disease) :: ['metastatic melanoma']
