Abstract CT012: Phase 1 trial of first-in-class ATR inhibitor VX-970 in combination with cisplatin (Cis) in patients (pts) with advanced solid tumors (NCT02157792)

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.CT012-CT012
• Main Authors: Shapiro, Geoffrey, Wesolowski, Robert, Middleton, Mark, Devoe, Craig, Constantinidou, Anastasia, Papadatos-Pastos, Dionysis, Fricano, Marjorie, Zhang, Yanqiong, Karan, Sharon, Pollard, John, Penney, Marina, Asmal, Mohammed, Renshaw, F. Gary, Fields, Scott Z., Yap, Timothy A.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-CT012

Background: 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). CohortVX-970 dose (mg/m2)Cis dose (mg/m2)No. pts treated/No. pts evaluable for dose limiting toxicities (DLTs)DLTs190403/32140404/33210404/442106010/101 (grade 3 elevated ALT)5140757/61 (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