Background: ATR mediates the homologous recombination DNA repair pathway and cellular response to replication stress. VX-970 is a potent and selective inhibitor of ATR (Ki <0.2 nM) that showed enhanced synergy of ATR inhibition with cytotoxic chemotherapy and potential mono ATR inhibitor activity in tumor cell lines with high levels of replication stress, such as defects in the DNA damage repair (DDR) pathway (e.g. ATM loss). A phase I dose-escalation trial of VX-970 (sponsored by Vertex Pharmaceuticals Incorporated) was undertaken to assess the safety and tolerability of an ATR inhibitor as mono and with DNA-damaging chemotherapy, to show evidence of ATR inhibition in tumor tissue, and to explore antitumor activity.
Methods: Pts with advanced solid tumors enrolled in 2 sequential parts. Part A: pts received IV VX-970 mono weekly in single-pt cohorts, with 3+3 cohorts initiated if grade (G) ≥2 VX-970-related adverse events (AEs) were observed. Part B: pts received CP on day 1 and VX-970 on days 2 and 9 of a 21-day cycle in a 3+3 dose-escalation design. Paired VX-970 tumor biopsies were obtained in selected CP treated pts pre- and post-VX-970, and pS345 Chk1 levels assessed by IHC.
Results: 25 pts were treated; M/F 10/15; median age 67 yr (range 49-76 yr); ECOG PS 0/1: 11/14. In Part A, 11 pts (colorectal [CRC; n = 2]; mesothelioma [n = 2]; other [n = 7]; median prior lines of therapy = 3) received VX-970 at 60 mg/m2 (n = 1), 120 mg/m2 (n = 2), 240 mg/m2 (n = 1) and 480 mg/m2 (n = 7). In Part B, 14 pts (CRC [n = 6]; ovarian [n = 2]; other [n = 6]; median prior lines of therapy = 3) received VX-970 240 mg/m2 + CP AUC5 (n = 3; dose level 1 [DL1]), VX-970 120 mg/m2 + CP AUC5 (n = 3; DL2), VX-970 120 mg/m2 + CP AUC4 (n = 3; DL3) and VX-970 90 mg/m2 + CP AUC5 (n = 5; DL4). In Part A, no dose-limiting toxicities (DLT) or drug-related G3-4 AEs were seen. In Part B, 2 pts had DLT: G4 neutropenia and fever (n = 1; DL1) and G3 hypersensitivity (n = 1; DL2). Non-DLT G3-4 AEs were neutropenia (n = 4; DL1-2) and thrombocytopenia (n = 1; DL2) requiring dose delays. No G3-4 AEs were seen at DL3-4. RP2D cohort expansion is ongoing at DL4. VX-970 displayed linear AUC and Cmax at all DLs; median half-life was 16h with no accumulation. Based on preclinical models, efficacious exposures were achieved. When combined with CP, DL1 and DL2 showed similar VX-970 exposure, suggesting no apparent drug interactions. Decreased Chk1 phosphorylation was seen in 2/2 paired tumor biopsies (74% at DL4; 94% at DL2). An advanced CRC pt (serosal disease and abdominal lymphadenopathy; 3 prior lines of chemotherapy) with complete ATM loss by IHC achieved RECIST complete response to VX-970 mono at 60 mg/m2 and remains on trial at 59+ wks. RECIST stable disease (SD) was seen with VX-970 mono in 4 pts (median duration of SD = 11 wks [11-17.4 wks]) and VX-970 + CP in 7 pts, who were still ongoing (duration of SD = 5+ to 20+ wks), including several pts who had progressed on prior platinum therapy.
Conclusion: VX-970 is well tolerated as monotherapy and in combination with CP, with preliminary evidence of target modulation and antitumor activity. VX-970 will be further explored in early phase II studies; in multiple tumor types, including triple-negative breast cancer and non-small cell lung cancer; and in patients with DDR aberrations.
Citation Format: Timothy A. Yap, Maria J. de Miguel Luken, Brent O'Carrigan, Desam Roda, Dionysis Papadatos-Pastos, David Lorente, Nina Tunariu, Raquel Perez Lopez, Sasha Gayle, Ruth Riisnaes, Ines Figueiredo, Susana Miranda, Suzanne Carreira, Fang Yang, Sharon Karan, Marina Penney, John Pollard, L. Rhoda Molife, Udai Banerji, Mohammed Asmal, Scott Z. Fields, Johann S. de Bono. Phase I trial of first-in-class ataxia telangiectasia-mutated and Rad3-related (ATR) inhibitor VX-970 as monotherapy (mono) or in combination with carboplatin (CP) in advanced cancer patients (pts) with preliminary evidence of target modulation and antitumor activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR14.