REFINE (REduced Frequency ImmuNE checkpoint inhibition in cancers): A multi-arm phase II basket trial testing reduced intensity immunotherapy across different cancers.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionised treating advanced cancers. ICI are administered intravenously every 2-6 weeks for up to 2 years, until cancer progression/unacceptable toxicity. Physiological efficacy is observed at lower doses than those used as standard of care (SOC). Pharmacodynamic studies indicate sustained target occupancy, despite a pharmacological half-life of 2-3 weeks. Reducing frequency of administration may be possible without compromising outcomes. The REFINE trial aims to limit individual patient exposure to ICI whilst maintaining efficacy, with potential benefits in quality of life and reduced drug treatment/attendance costs. METHODS/DESIGN: REFINE is a randomised phase II, multi-arm, multi-stage (MAMS) adaptive basket trial investigating extended interval administration of ICIs. Eligible patients are those responding to conventionally dosed ICI at 12 weeks. In stage I, patients (n = 160 per tumour-specific cohort) will be randomly allocated (1:1) to receive maintenance ICI at SOC vs extended dose interval. REFINE is currently recruiting UK patients with locally advanced or metastatic renal cell carcinoma (RCC) who have tolerated and responded to initial nivolumab/ipilimumab, randomised to receive maintenance nivolumab SOC (480 mg 4 weekly) vs extended interval (480 mg 8 weekly). Additional tumour cohorts are planned. Subject to satisfactory outcomes (progression-free survival) stage II will investigate up to 5 different treatment intervals. Secondary outcome measures include overall survival, quality-of-life, treatment-related toxicity, mean incremental pathway costs and quality-adjusted life-years per patient. REFINE is funded by the Jon Moulton Charity Trust and Medical Research Council, sponsored by University College London (UCL), and coordinated by the MRC CTU at UCL. Trial Registration ISRCTN79455488. NCT04913025 EUDRACT #: 2021-002060-47. CTA 31330/0008/001-0001; MREC approval: 21/LO/0593. REFINE Protocol version 4.0.

Ambrosia Beetle Occurrence and Phenology of Xylosandrus spp. (Coleoptera: Curculionidae: Scolytinae) in Ornamental Nurseries, Tree Fruit, and Pecan Orchards in Georgia.

Ambrosia beetles (Coleoptera: Curculionidae: Scolytinae, Platypodinae) in the genus Xylosandrus are problematic in ornamental nurseries and are emerging as serious pests in orchard crops. An updated survey of ambrosia beetles focusing on these damaging species, and their corresponding phenology was conducted in Georgia to aid in refining management practices for these beetles. Ambrosia beetles were monitored across nine sites in 2019 and seven sites 2020 at ornamental nurseries, tree fruit, and pecan orchards in Georgia. At each site, six ethanol-baited bottle traps were deployed; with three traps along the edge of a wood-line and three traps placed 30 m from the edge of the nurseries and orchards. Traps were deployed from mid-January through July or August depending on site and year. All captured ambrosia beetles were counted and identified. Captures of X. crassiusculus, X. germanus, and X. compactus, were analyzed further to investigate spatial distribution and seasonal flight activity. At high population sites, more beetles were captured along adjacent wood lines than in the orchard or nursery interior. At most sites, flight activity began in February and March continued until the termination of the study in July or August. At most sites, sustained flight activities with multiple peaks were observed in March, April, and May, corresponding to average weekly temperatures reaching ≥15.5°C. These results have important implications on temporally and spatially precise management for these beetles across three important agricultural production systems in the southeastern US.