医学
吉西他滨
最大值
化疗
实体瘤疗效评价标准
乳腺癌
临床研究阶段
癌症
内科学
肿瘤科
药代动力学
药理学
作者
Elizabeth Ruth Plummer,Emma Dean,Evans Trj.,Alastair Greystoke,Karin H Herbschleb,Malcolm R Ranson,Jennifer R. Brown,Y Zhang,Sharon Karan,John R. Pollard,Marina Penney,Mohammed Asmal,SZ Fields,Mark R. Middleton
标识
DOI:10.1200/jco.2016.34.15_suppl.2513
摘要
2513 Background: ATR is a regulator of the cellular response to replication stress, where it signals DNA damage repair through the homologous recombination pathway.Many cancer cells depend on ATR to survive DNA damage. VX-970 is a potent, selective inhibitor of ATR with marked preclinical anticancer activity in combination with DNA-damaging chemotherapy in preclinical models. A multicenter phase I study of VX-970 in combination with Gem was performed. Methods: Patients (pts) with advanced solid tumors measurable by RECIST 1.1 received IV VX-970 in combination with Gem in a 3+3 dose-escalation design. Gem was administered on days 1 and 8 and VX-970 on days 2, 9 and 16 of each 21-day cycle. Results: 50 pts were treated (28 M/22 F), median age 62 yrs (range 28-79 yrs), ECOG PS 0/1: 15/35. Primary tumors were colorectal (n=15), NSCLC (n=6), breast (n=4), pancreatic (n=2) and other (n=23). Gr 3/4 treatment-related AEs occurred in 25 pts. Maximum tolerated dose was not reached. VX-970 exposure was approximately linear based on Cmax and AUC0-∞ ; terminal T1/2 was ≈16 h. Best response was PR in 4 pts (breast, NPC, NSCLC, and CUP). Two pts with cancers not typically responsive to chemotherapy had prolonged SD: PFS was 415 days (papillary ca) and >191 days (GIST). Exposures achieved at ≈90mg/m2 correlated to those showing maximum preclinical activity. In a parallel phase I study this dose blocked ATR activity by ≈75% in patient tumor biopsies. Preliminary data from a non-randomized comparison of cohorts 1-4 (VX-970 < 90mg/m2 with Gem 875 mg/m2) and 5-7 (VX-970 ≥ 90mg/m2 with Gem 500mg/m2) showed median PFS of 8.3 and 29.3 weeks, respectively. Conclusions: The recommended phase II dose is VX-970 210 mg/m2 and Gem 1000 mg/m2. Preliminary evidence of activity was observed. Studies in biomarker-defined NSCLC and SCLC are ongoing, as are additional studies with VX-970 and platinum in TNBC. Clinical trial information: NCT02157792.Cohort VX-970 dose (mg/m2) Gem dose (mg/m2) No. pts treated/No. pts evaluable for DLTs No. DLTs (DLT) 1 18 875 3/3 2 36 875 3/3 3 60 875 4/3 4 72 875 7/6 2 (gr 3 thrombocytopenia; gr 3 elevated ALT and fatigue) 5 90 500 6/6 1 (gr 3 elevated AST) 6 140 500 8/6 1 (gr 3 elevated AST and ALT, gr 2 elevated ALP) 7 210 500 3/3 8 210 750 3/3 9 210 875 7/6 10 210 1000 6/6
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