Phase I modular study of AZD6738, a novel oral, potent and selective ataxia telangiectasia Rad3-related (ATR) inhibitor in combination (combo) with carboplatin, olaparib or durvalumab in patients (pts) with advanced cancers

Background: AZD6738 is a potent, selective oral ATR inhibitor that: (i) potentiates DNA damage induced by carboplatin (Carbo) or the PARP inhibitor olaparib (Ola) by inhibiting ATR‐dependent cell cycle checkpoint and repair; (ii) may sensitise cancers to immune checkpoint inhibitors such as durvalumab (Durva). Study D5330C00004 is a Phase I modular study in which AZD6738 is combined with these 3 agents. Material and Methods: A Phase I dose escalation trial assessing AZD6738 in three combo modules with: (i) Carbo AUC5 IV day 1 and repeated every 21 days (AZD6738+Carbo); (ii) Ola tablets bd (AZD6738+Ola); (iii) Dur 1500 mg IV every 4 weeks (AZD6738+Durva). Pharmacokinetic (PK) and pharmacodynamic evaluations were conducted. Results: To date, 69 pts with advanced cancers have been treated in 3 combo modules: AZD6738+Carbo (33 pts); AZD6738+Ola (27 pts); AZD6738+Dur (9 pts). Tumour types included advanced HGSOC, HNSCC, TNBC, NSCLC, SCLC, mesothelioma, cervical and colorectal cancers. AZD6738+Carbo module: 6 doses/schedules of AZD6738 were assessed with Carbo, from 20 mg bd D2‐17, to 60 mg bd for 3 days starting on D1 after Carbo ('co‐dosing'). AZD6738+Carbo toxicities included thrombocytopenia (>Gr3 in 12 pts ‐ schedule limiting); neutropenia (>Gr3 in 9 pts) and anaemia (>Gr3 in 11 pts), leading to dose/schedule modifications. When given on D1 after Carbo, AZD6738 at 40 mg bd for 2 days appears tolerable and is being explored as a potential Phase II regimen. 3 RECIST partial responses (PR) were observed with co‐dosing of AZD6738+Carbo in pts with advanced cervical cancer, ATM‐loss rectal cancer and ATM mutant clear cell ovarian cancer (unconfirmed PR). AZD6738+Ola module: 5 doses/schedules of AZD6738 and/or Ola were assessed, starting at 60 mg od AZD6738 D1‐5 and D15‐19 with Ola 100 mg bd D1‐28. With shorter AZD6738 regimens, the Ola combo was well tolerated with the only >Gr3 toxicity of neutropenia. When AZD6738 was extended to 14 days, DLTs occurred [Gr4 thrombocytopenia (n = 1) and >Gr3 neutropenia (n = 2)]. Dose Level 5 (160 mg od AZD D1‐7 + 300 mg bd Ola D1‐28) is being assessed as a potential Phase II regimen. 2 BRCA mutant TNBC pts achieved RECIST PRs. AZD6738+Durva module: AZD6738 was given as 80 mg bd days 1‐14 monotherapy run‐in, then AZD6738 80 mg bd D22‐28 + Durva 1500 mg on D1 and D28. Gr1‐2 immune toxicities and nausea/vomiting, but no DLTs have been reported. 2 RECIST PRs were observed, one in a squamous cell carcinoma of larynx pt and another in a NSCLC pt for which confirmation of complete response is awaited. Preliminary PK of AZD6738 show rapid absorption, peak plasma concentration after 1.5 h and t1/2 of 11 h. AZD6738 plasma concentrations increased dose proportionately. Conclusions: The combinations of the oral ATR inhibitor AZD6738 with Carbo, Ola and Durva are feasible, with preliminary signals of anti‐tumour activity observed in all combo modules.