O3.6Combination of @entity4041 inhibitor onalespib with XXXX to treat or delay resistance in @entity1149 : Preclinical and Clinical Investigations.

@entity1 @entity4041 @entity5 @entity9816 @entity1149 @entity57649 @entity294 @entity14
UNASSIGNED: Although @entity9816 (CZ) has clinical activity in ALK (+) @entity1149 ( @entity1149 ), relapse is common due to the development of resistance. ALK and components of signalling pathways involved in resistance are client proteins of the chaperone, @entity4041 , offering an alternative method for targeting the disease. Onalespib[ @entity14 ]( @entity57649 ), a potent 2nd generation @entity4041 inhibitor had anti- @entity5 activity in CZ-sensitive and CZ-resistant xenograft models when combined with CZ (Courtin et al). Importantly, when combined upfront with CZ in a CZ-sensitive xenograft model, @entity14 delayed the emergence of resistance observed with CZ monotherapy (Smyth et al.). These preclinical data suggest therapeutic potential for an @entity14 /CZ combination in CZ-sensitive and -resistant disease. This is currently being investigated in a 3-part Phase1/2 randomised @entity1149 study. The primary objectives of the Phase 1 part of the clinical study were the safety and tolerability of CZ and @entity14 and selection of the recommended phase 2 dose (RP2D) of @entity14 . A rolling six design was used to determine the maxiumum tolerated dose (MTD)/RP2D of the combination. @entity1 received 250 mg BID oral CZ and IV @entity14 weekly for 3 of 4 weeks of a 28 day cycle (dosing cohorts 150, 180 or 220 mg/m(2)). In Part A, 32 @entity1 , who had prior CZ treatment, were treated with the combination in 3 dosing cohorts. @entity14 was escalated up to 220 mg/m(2) without DLTs and the combination was well tolerated ( @entity294 was the only @entity14 -related AE >=  Grade 3 in > 5% of @entity1 ). The mean number of @entity14 cycles was 4.2 (range 1-11+). @entity14 exposures were similar to previous studies and CZ exposures were unaffected when co-administered with @entity14 . Of 25 evaluable @entity1 , there were 4 PR and over 50% of subjects had a decrease in @entity5 size. CZ/ @entity14 doses of 250 mg BID/220 mg/m(2) were selected as the combination RP2D (Besse et al.). Preclinical data suggest that a CZ/ @entity14 combination has potential, upfront, to delay the emergence of resistance to CZ or, after relapse, to overcome resistance. A RP2D has been selected to continue evaluation of these hypotheses in Phase 2 studies of this combination in @entity1 prior to or after progression on CZ.
