AZD6738 is a potent oral selective inhibitor of ATR (ataxia telangiectasia Rad3-related). The ongoing dose escalation Phase I study D5330C00004 (NCT02264678) combines AZD6738 with Durvalumab (Durva) to exploit ATR-dependent cycle arrest and DNA damage-induced immune responses.
Five 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 have completed (cohort 6 is ongoing), with concurrent translational blood borne and biomarker assessment.
Twenty-five pts have been treated to date with either NSCLC, or HNSCC cancer. Toxicities that occurred 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, an on-target AZD6738 effect. Of 21 pts, 1 RECIST CR, 2 PRs and 1 uPR were observed in advanced NSCLC (3 pts) and HNSCC (1 pt) with no clear correlation with tumor PD-L1 or ATM expression. Expansion of the final cohort 6 is ongoing with one reported DLT in the initial 3 of the planned 6 pts. 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 Durva.
Peripheral monocytes and proliferating T-cells were suppressed during the AZD6738 dosing interval; both rebounding to levels ≥ baseline during the off-drug interval; the immunostimulatory cytokine IL-12 behaved similarly. These cyclical changes were observed across multiple treatment cycles. GM-CSF increased reciprocally to on-target decreases in monocytes. Durvalumab was dosed to saturation and therefore these changes are attributable to AZD6738. AZD6738 consistently increased pRAD50 in post treatment tumour biopsies.
The combination of AZD6738 with Durva was tolerated in dose escalation with signals of antitumor activity and pharmacodynamic evidence of AZD6738 target engagement.
Clinical trial identification
Legal entity responsible for the study
Y-J. Bang: Consultancy work: AstraZeneca plc; Research funding to institution: AstraZeneca. W. Abidah: Consulting: Clovis Pharmaceuticals. L.T. Khoja, G.N. Jones, P. Marco-Casanova: Full time employee: AstraZeneca plc. N. Standifer: Full time employee: Medimmune/AstraZeneca plc. P. Frewer, A. Berges, A. Cheung, C. Stephens, B. Felicetti, E. Dean, A. Pierce, S. Hollingsworth: Full time employee and shareholder: AstraZeneca plc. All other authors have declared no conflicts of interest.