Abstract CT026: 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

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.

Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells

“…With all schedules, combined treatment reduced tumour growth, whereas single-agent treatments provided little benefit over the control. These data highlight the importance of dose scheduling combination treatments to balance efficacy and tolerability, and suggest tumour growth inhibition can be achieved with as little as a 3 or 5-day treatment window [45,47]. Note that due to frequent ulcerations of the FaDu ATM-KO xenograft model affecting animal well-being, only a short-term (21 days) 5 days on 9 days off olaparib/AZD6738 combination regimen could be performed.…”

Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer

“…Then, we selected AZD6738 at 30 mg/kg (daily, oral gavage) and belotecan at 10 mg/kg (every 4 days, intraperitoneally) for single or combination dosages. However, two mice died in the combination group between 10 and 23 days and the remaining lost weight at an average of 1.7 g. Therefore, starting on day 42 we changed the dosing schedule of AZD6738 from daily dosing to 2 days on and 2 days off by referencing the human phase I trial of combined AZD6738 (7 days on/21 days off) and olaparib [ 25 ]. After intermittent dosing, the weight loss was reduced to an average of 1.1 g per mouse ( Figure 5 a).…”

“…If a clinical trial is designed with this combination, we recommend that AZD6738 be administered intermittently with belotecan. Furthermore, in the previous phase I trial of combined AZD6738 and olaparib, AZD6738 was safely given in an intermittent mode of 7 days on/21 days off [ 25 ]. There have been one published and three ongoing phase I trials with another ATR inhibitor, VX-970 (M6620; Vertex Pharmaceuticals, Boston, MA, USA), in combination with a topoisomerase inhibitor, topotecan or irinotecan, as listed in Supplementary Table S2 .…”

Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer

“…Ceralasertib (P.O.) was well tolerated in monotherapy (RP2D assessed as 160 mg) [ 121 ], or in combination with carboplatin (RP2D assessed as 40 mg of ceralasertib), olaparib (RP2D = 160 mg of ceralasertib), and durvalumab (RP2D = 80–240 mg of ceralasertib) [ 122 , 123 ]. Among DLTs (G3/4) thrombocytopenia and neutropenia mostly occurred in combination with carboplatin and olaparib, respectively.…”

“…Among DLTs (G3/4) thrombocytopenia and neutropenia mostly occurred in combination with carboplatin and olaparib, respectively. Higher responses were evident in ATM-deficient cancers for the carboplatin group, and in BRCA1/2 -mutated cancers for the olaparib-treated group where responses were independent of ATM status [ 122 , 123 ]. Moreover, PRs and several prolonged SDs were confirmed for monotherapy [ 121 ].…”