Discussion
SCLC, aggressive lymphomas, neutropenia, tumours, toxicities, SD, bone marrow and gastrointestinal toxicities, extensive-stage, RB1 deficiency, BRCA2 deletion/duplication
OVARIAN CANCER, SOLID TUMOUR, SCLC, NEUTROPENIA, TUMOURS, PROLIFERATION
In the dose-escalation phase of this first-in-human study, AZD2811 was assessed in 12 cohorts; the MTD and RP2D were determined to be 500 mg on Day 1 of a 21-day cycle with mandatory combination G-CSF. Administration of AZD2811 only on Day 1 of each cycle (rather than on Days 1 and 4) was implemented alongside the addition of G-CSF prophylaxis with the aim of managing recovery from neutropenia and improving patient convenience, and may also facilitate potential combinations with other treatments in future studies. A cycle length of 21 days rather than 28 days was deemed to be preferable to minimise the fall in drug concentrations below the active level between cycles; this increase in dose intensity was considered particularly important for the treatment of patients with rapidly growing tumours such as SCLC, ovarian cancer, and aggressive lymphomas. Mandatory G-CSF (administered on Day 8 of each cycle) minimised the impact of treatment-related neutropenia/decreased neutrophil count at higher doses. The MTD/RP2D was investigated in the expansion phase of this study (to be published separately) in patients with previously treated SCLC (both limited-stage [LS] and extensive-stage [ES]), whose tumours are expected to be sensitive to AURKB inhibition due to the characteristic rapid proliferation and reliance on accelerated mitosis of SCLC. The dosing schedule assessed in Cohort 6 (200 mg AZD2811 on Days 1 and 4 every 28 days) was also explored in the N3 cohort of the SCLC Umbrella Korea Studies (SUKSES-N3), a phase 2 trial of second- or third-line therapy for LS- or ES-SCLC. There were no objective responses but 5/15 (33.3%) patients had SD [In previous phase 1 studies in patients with advanced solid tumours, AURKB inhibitors have been generally well tolerated, with bone marrow and gastrointestinal toxicities typically being the most common AEs [Based on the key role of AURKB in mitosis, neutropenia and decreased neutrophil count are expected toxicities of treatment with AURKB inhibitors due to the rapid rate of cell division in bone marrow neutrophils [Other AURKB inhibitors have demonstrated limited antitumour activity in phase 1 studies in patients with advanced solid tumours. For example, with BI 831266, 1 patient (4%) experienced a PR and 4 patients (16%) had SD [With respect to the patient with PR, we hypothesise that the RB1 mutation or the BRCA2 deletion/duplication may be the most relevant alterations associated with this patient’s response, as synthetic lethality between RB1 deficiency and Aurora B kinase inhibitors [Analyses of PK data demonstrated that maximum AZD2811 whole blood concentrations were observed after drug infusion. The long-circulating nanoparticle formulation provided more sustained and extended total AZD2811 blood exposure compared with historical measurements in barasertib clinical studies [This study has some limitations. This efficacy analysis was limited by the small and heterogeneous population that prevented reliable identification of subgroups of patients who may respond to AZD2811. At the time of study initiation, there were no predictive biomarkers for AURKB inhibitors, but research is underway to identify potential biomarkers and molecularly defined patient subsets who may be sensitive to AZD2811 [In conclusion, 500 mg of AZD2811 in a 21-day cycle dosed on Day 1, with G-CSF support on Day 8, was tolerable in patients with advanced solid tumours. On-target neutropenia was a pharmacodynamic biomarker and was manageable with the addition of G-CSF. This RP2D has been investigated in the dose-expansion phase of the study in patients with SCLC and will be published separately (Johnson et al., manuscript in preparation).