Phase I trial of a first-in-class ATR inhibitor VX-970 as monotherapy (mono) or in combination (combo) with carboplatin (CP) incorporating pharmacodynamics (PD) studies.

2504Background: ATR is a regulator of cellular responses to replication stress, where it signals DNA damage repair by homologous recombination. Many cells depend on ATR to survive DNA damage. VX-970 is a potent, selective ATR inhibitor with marked preclinical antitumor activity in combo with chemotherapy. Methods: Patients (pts) with advanced cancers were enrolled in 2 parts. Part A: N=1 pt cohorts received VX-970 QW; 3 + 3 cohorts were commenced if ³ G2 drug-related toxicities occurred. Part B: 3 + 3 pt cohorts received CP on d1 + VX-970 on d2 and 9 in 21-day cycles. Timed pre- and post-VX-970 tumor biopsies were assessed for pS345 CHK1 levels by IHC in part B. Hematologic toxicities were modeled for pts in part B. Results: 26 pts were treated; M/F 10/16, ECOG PS 0/1: 9/17. Median age: 66 yrs (range 49-76 years). VX-970 was generally well tolerated as mono or CP combo with mainly G1-2 toxicities. CP dose delays and reductions occurred in 3/3 pts (B1); 2/2 pts (B2); 0/3 pts (B3); 1/6 pts (B4) due to neutr...