Background: AZD6738 is a potent selective oral ATR inhibitor. Therapeutic combinations aim to inhibit ATR-dependent cycle arrest and repair induced by the PARP inhibitor Olaparib (Ola), and to exploit DNA damage-induced immune responses with the anti-PD-L1 antibody Durvalumab (Durva). Here we present the results of the ongoing Phase I study D5330C00004 (NCT02264678) dose escalation combinations of AZD6738 with Ola or Durva.
Methods: A trial assessing AZD6738 in combination with continuous Ola tablets or Durva IV infusion per 28-day cycle. Pharmacokinetic (PK) and pharmacodynamic evaluations were conducted.
Results: 70 pts with advanced cancer were treated with +Ola (45 pts) or +Durva (25 pts). Tumor types included breast, ovary, prostate, pancreas, lung, HNSCC and gastric cancers. +Ola: AZD6738 was assessed in 10 cohorts from 60 mg od to 240 mg bd for 5-14 days (D), co-dosing with Ola 100-300 mg bd continuously. All causality toxicity occurring in ≥20% subjects (pts with ≥G3 events) included: thrombocytopenia (5 pts), anemia (7 pts), neutropenia (6 pts), fatigue (1 pt), decreased appetite (1 pt), nausea, vomiting, constipation, diarrhea and cough. Thrombocytopenia and neutropenia were dose- and schedule limiting toxicities (DLTs). The Recommended Phase 2 Dose is AZD6738 160 mg od D1-7 + Ola 300 mg bd D1-28. Of 39 evaluable pts, 1 RECIST complete response (CR), 5 partial responses (PR) and 1 unconfirmed (uPR) were observed in pts with advanced breast (3 pts), ovarian, prostate, pancreatic and ampullary cancer and BRCA1/2 mutations independent of ATM status. Dose expansions are ongoing in pts with advanced gastric and breast cancer. +Durva: AZD6738 was evaluated in 5 cohorts with 1-2 weeks monotherapy run-in, followed by Durva 1500 mg on D1 + AZD6738 80-240 mg od or bd for 1 (D22-28) or 2 (D15-28) weeks. Toxicity occurring in ≥20% subjects included: anemia (≥G3 in 1 pt), fatigue, nausea, decreased appetite, cough, vomiting, dizziness, pruritus, constipation, diarrhea, musculoskeletal chest pain and dyspnea. One DLT of thrombocytopenia was observed. Of 21 pts, 1 RECIST CR, 2 PRs and 1 uPR were observed in pts with advanced NSCLC (3 pts) and HNSCC (1 pt), independent of tumor PD-L1 expression. Peripheral monocytes and proliferating T-cells were suppressed; both rebounding to levels ≥ baseline during the off-drug interval. GM-CSF increased reciprocally to on-target decreases in monocytes. Preliminary PK data showed rapid absorption of AZD6738 with peak plasma concentration ≈1.5h post dose, a biphasic decline with an elimination half-life of 11h. Despite ≈45% variability in clearance, there was dose proportionality and no evidence of drug-drug interaction with Ola or Durva.
Conclusions: The combinations of AZD6738 with Ola or Durva were tolerated in dose escalation with preliminary signals of antitumor activity in pts with advanced solid tumors.
Citation Format: Matthew G. Krebs, Juanita Lopez, Anthony El-Khoueiry, Yung-Jue Bang, Sophie Postel-Vinay, Wassim Abida, Louise Carter, Wen Xu, Seock-Ah Im, Andrew Pierce, Paul Frewer, Alienor Berges, S.Y. Amy Cheung, Christine Stephens, Brunella Felicetti, Emma Dean, Simon J. Hollingsworth. Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT026.