Abstract 3717: Defining optimal dose schedules for ATR inhibitors in combination with DNA damaging drugs: Informing clinical studies of VX-970, the first-in-class ATR inhibitor
Authors: Pollard John , Reaper Phil , Peek Adele , Hughes Stuart , Gladwell Scott , Jones Julie , Chiu Peter , Wood Mark , Tolman Crystal , Johnson Mac , Littlewood Peter , Penney Marina , McDermott Katherine , Hare Brian , Fields Scott Z. , Asmal Mohammed , O’Carrigan Brent , Yap Timothy A. 
Published: July 2016

Abstract
Proficient repair of DNA damage is a cause of the poor response many patients experience when treated with commonly used DNA-damaging drugs such as cisplatin, carboplatin and gemcitabine. The protein kinase ataxia telangiectasia mutated and Rad3 related (ATR) is recruited to DNA damage lesions caused by such drugs during the S and G2 phase of cell cycle, where it coordinates a series of responses including checkpoint activation and DNA repair by homologous recombination.
Inhibition of ATR potentiates the cytotoxic activity of DNA damaging drugs in many cancer cells. In stark contrast, non-cancer cells survive inhibition of ATR with just transient growth arrest. Cancer cells carrying common defects in a compensatory repair pathway mediated by the kinase ataxia telangiectasia mutated (ATM) and its principle substrate, p53, are especially sensitive to ATR inhibition. Two ATR inhibitors are in clinical development in combination with DNA damaging drugs, however a comprehensive assessment of dose schedule considerations has not been reported.
In pre-clinical models, the efficacy of an ATR inhibitor in combination with multiple DNA damaging drugs was shown to be dependent on dose schedule. In vitro, transient exposure of cancer cells to an ATR inhibitor (2 hours) was highly effective when added after the DNA damaging drug. Maximum activity was observed when addition of the ATR inhibitor was timed to coincide with peak accumulation of cells in S-phase and concomitant activation of ATR (P-Chk1), following treatment with the DNA damaging drug. In mouse xenograft models, strong synergistic activity was achieved from just a single dose of the ATR inhibitor given once per cycle of the DNA damaging drug.
Optimal efficacy was achieved by administering the ATR inhibitor 12-24 hours after the DNA damaging drug. Dosing the ATR inhibitor prior to, or greater than 48 hours after, the DNA damaging drug provided limited benefit. On this schedule, addition of the ATR inhibitor had minimal impact on the tolerability profile of the DNA damaging drug. VX-970, the first-in-class ATR inhibitor, is being assessed as monotherapy and in combination with gemcitabine, cisplatin and carboplatin in Ph1/2 clinical studies. Based on pre-clinical data, VX-970 is being dosed approximately 24 hours after the DNA damaging drug. Preliminary tumor biomarker data from three patients showed high P-Chk1 24 hours after treatment with carboplatin, which is inhibited by VX-970.
These data suggest the importance of dose scheduling on the efficacy of ATR inhibitors and DNA damaging drug combinations and inform the design of ongoing clinical studies.
Citation Format: John Pollard, Phil Reaper, Adele Peek, Stuart Hughes, Scott Gladwell, Julie Jones, Peter Chiu, Mark Wood, Crystal Tolman, Mac Johnson, Peter Littlewood, Marina Penney, Katherine McDermott, Brian Hare, Scott Z. Fields, Mohammed Asmal, Brent O’Carrigan, Timothy A. Yap. Defining optimal dose schedules for ATR inhibitors in combination with DNA damaging drugs: Informing clinical studies of VX-970, the first-in-class ATR inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3717.