Phase 1 Trial Of First-In-Class Atr Inhibitor Vx-970 In Combination With Cisplatin (Cis) In Patients (Pts) With Advanced Solid Tumors (Nct02157792)

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LABackground : 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.Methods : Pts received intravenous VX-970 in combination with Cis using a 3+3 dose escalation design. Cis was administered on day 1 and VX-970 on days 2 and 9 in 21-day cycles.Results : 28 pts were treated (12 M/16 F); median age 62.5 yrs (range 28-79 yrs) and ECOG PS 0-1. Primary tumors were colorectal (n = 5), breast (n = 4), ovarian (n = 3), pancreatic (n = 2), and other cancers (n = 14). Cohort | VX-970 dose (mg/m2) | Cis dose (mg/m2) | No. pts treated/No. pts evaluable for dose limiting toxicities (DLTs) | DLTs ||:------ | ------------------- | ---------------- | --------------------------------------------------------------------- | --------------------------------- || 1 | 90 | 40 | 3/3 | || 2 | 140 | 40 | 4/3 | || 3 | 210 | 40 | 4/4 | || 4 | 210 | 60 | 10/10 | 1 (grade 3 elevated ALT) || 5 | 140 | 75 | 7/6 | 1 (grade 3 drug hypersensitivity) |Non-DLT grade 3-4 treatment-related adverse events occurred in 11 pts, including nausea, cytopenias, hypotension, hypoalbuminemia, hypokalemia, elevated LFTs, and drug hypersensitivity. Maximum tolerated combination dose was not reached; dose escalation was stopped because pharmacokinetic (PK) exposures of VX-970 at 140 mg/m2 exceeded levels previously shown in preclinical models to result in robust target engagement and tumor regression in combination with Cis. There was no effect of Cis on VX-970 PK. Terminal elimination half-life was ?16h and PK was proportional across the dose range. Among pts who received VX-970 at 140 mg/m2 with Cis, preliminary results showed RECIST partial responses in 4 pts: 3 platinum-resistant/refractory (mesothelioma, ovarian and TNBC) and 1 ongoing unconfirmed response in a pt in which platinum sensitivity is currently unknown (neuroendocrine prostate cancer).Conclusions: The recommended phase 2 dose is VX-970 140 mg/m2 and Cis 75 mg/m2 with RECIST antitumor responses observed including platinum-refractory/resistant pts. Combination studies involving pts with biomarker-defined NSCLC (gemcitabine) and TNBC (platinum) are ongoing.Citation Format: Geoffrey Shapiro, Robert Wesolowski, Mark Middleton, Craig Devoe, Anastasia Constantinidou, Dionysis Papadatos-Pastos, Marjorie Fricano, Yanqiong Zhang, Sharon Karan, John Pollard, Marina Penney, Mohammed Asmal, F. Gary Renshaw, Scott Z. Fields, Timothy A. Yap. Phase 1 trial of first-in-class ATR inhibitor VX-970 in combination with cisplatin (Cis) in patients (pts) with advanced solid tumors ([NCT02157792][1]). [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 CT012. [1]: /lookup/external-ref?link_type=CLINTRIALGOVu0026access_num=NCT02157792u0026atom=%2Fcanres%2F76%2F14_Supplement%2FCT012.atom