Initial testing (stage 1) of M6620 (formerly VX-970), a novel ATR inhibitor, alone and combined with cisplatin and melphalan, by the Pediatric Preclinical Testing Program

BackgroundM6620 is a novel inhibitor of the DNA damage repair enzyme ATR, and has potentiated the activity of cisplatin and irinotecan in non-small cell lung cancer and colon cancer xenografts, respectively. ProceduresM6620 was tested in vitro at concentrations ranging from 1.0nM to 10.0 M and at 75nM in combination with cisplatin or melphalan. M6620 was tested against 24 solid tumor xenografts alone and in combination with cisplatin. Cisplatin was administered intraperitoneally on days 1 and 8 at a dose of 5mg/kg. M6620 was administered intravenously on days 2 and 9 at 20mg/m(2) approximately 16hr after cisplatin. ResultsThe median relative IC50 (rIC(50)) value for M6620 was 0.19 M (range 0.03-1.38 M). M6620 reduced the mean IC50 of cisplatin and melphalan by 1.48- and 1.95-fold, respectively. M6620 as a single agent in vivo induced significant differences in event-free survival (EFS) distribution in 5 of 24 (21%) solid tumor xenografts, but induced no objective responses. Cisplatin as a single agent induced significant differences in EFS distribution compared to control in 18 of 24 (75%) solid tumor xenografts. Three objective responses to cisplatin were observed. The M6620 and cisplatin combination induced significant differences in EFS distribution compared to control in 21 of 24 (88%), with four objective responses. ConclusionsM6620 showed modest potentiation of cisplatin and melphalan activity for some cell lines. M6620 showed little single-agent activity and the addition of M6620 to cisplatin significantly prolonged time to event for a minority of tested xenografts across several histologies.