Results from a phase I, open-label study of ceralasertib (AZD6738), a novel DNA damage repair agent, in combination with weekly paclitaxel in refractory cancer (NCT02630199)

Abstract

Background: Ataxia Telangiectasia and Rad3 Related (ATR) is an apical kinase with a critical role in the DNA-damage response. During normal DNA replication, ATR is recruited at stalled replication forks which can progress to double strand breaks if left unrepaired. AZD6738 is an oral inhibitor of the serine/threonine protein kinase ATR, a member of the phosphoinositide 3-kinase related kinase (PIKK) family. Methods: Eligible patients (pts) with advanced solid tumours were administered AZD6738 in combination with fixed dose paclitaxel 80 mg/m2 D1, D8, D15 in 28-day cycles. The dose of AZD6738 was escalated to reach a maximum tolerated dose (MTD) in a rolling 6 design. The trial evaluated safety, MTD, pharmacokinetics (PK) and pharmacodynamics (PD). Translational studies on plasma samples included cytokine analysis, panel sequencing of ctDNA, as well as IHC and immunofluorescence of immune cell markers. Results: 58 pts (34 melanoma, 15 gastric cancer (GC), 4 sarcoma, 3 colon cancer, 1 neuroendocrine and 1 hepatocellular cancer) were enrolled in 7 dose cohorts ranging 40mg OD to 240 mg BID. One dose-limiting toxicity (DLT) of neutropenic fever occurred in each cohort of n = 6 evaluable pts at AZD6738 160 mg BD and 240 mg BD days 1-14. Per protocol, the maximum tolerated dose of AZD6738 is 240 mg BID days 1-14. The most common toxicities (all causality, all grade) were: anorexia/nausea (n = 15, 26%), leukopenia (n = 11, 19%) and anemia (n = 11, 19%). 51 pts are evaluable for efficacy; we observed 1 complete response (1.9 %, melanoma), 12 confirmed partial responses (23.5%; 2 gastric, 10 melanoma all of which were post-immunotherapy), 18 stable disease (35.3%) and 20 disease progression (39.2%). The overall confirmed response rate from the dose escalation is 25.5%. Genomic analysis of baseline plasma (27 pts) revealed enrichment of NF1 somatic mutations and activating NRAS mutations amongst melanoma pts (6/18 and 4/18, respectively). Cyclical changes in interleukin-12 levels were observed in three pts with disease control which could reflect an immunological component to the mechanism of response. We will present a comprehensive case report of a patient with dramatic and durable response. Conclusions: We conclude that AZD6738 can be safely combined with weekly paclitaxel and propose a recommended phase II dose and schedule. The combination of AZD6738 and paclitaxel demonstrated promising anti-tumor activity with durable responses, especially in melanoma pts after failing anti-PD1 therapy.