[¹8F]fluciclatide in the in vivo evaluation of human melanoma and renal tumors expressing αvß 3 and α vß 5 integrins.

PURPOSE: [(18)F]Fluciclatide is an integrin-targeted PET radiopharmaceutical. αvß3 and αvß5 are upregulated in tumor angiogenesis as well as on some tumor cell surfaces. Our aim was to use [(18)F]fluciclatide (formerly known as [(18)F]AH111585) for PET imaging of angiogenesis in melanoma and renal tumors and compare with tumor integrin expression. METHODS: Eighteen evaluable patients with solid tumors ≥2.0 cm underwent [(18)F]fluciclatide PET/CT. All patients underwent surgery and tumor tissue samples were obtained. Immunohistochemical (IHC) staining with mouse monoclonal antibodies and diaminobenzidine (DAB) was applied to snap-frozen tumor specimens, and additional IHC was done on formalin-fixed paraffin-embedded samples. DAB optical density (OD) data from digitized whole-tissue sections were compared with PET SUV80% max, and Patlak influx rate constant (K i) data, tumor by tumor. RESULTS: Tumors from all 18 patients demonstrated measurable [(18)F]fluciclatide uptake. At the final dynamic time-point (55 min after injection), renal malignancies (in 11 patients) demonstrated an average SUV80% max of 6.4 ± 2.0 (range 3.8 - 10.0), while the average SUV80% max for metastatic melanoma lesions (in 6 patients) was 3.0 ± 2.0 (range 0.7 - 6.5). There was a statistically significant difference in [(18)F]fluciclatide uptake between chromophobe and nonchromophobe renal cell carcinoma (RCCs, with SUV80% max of 8.2 ± 1.8 and 5.4 ± 1.4 (P = 0.020) and tumor-to-normal kidney (T/N) ratios of 1.5 ± 0.4 and 0.9 ± 0.2, respectively (P = 0.029). The highest Pearson's correlation coefficients were obtained when comparing Patlak K i and αvß5 OD when segregating the patient population between melanoma and RCC (r = 0.83 for K i vs. melanoma and r = 0.91 for K i vs. RCC). SUV80% max showed a moderate correlation with αvß5 and αvß3 OD. CONCLUSION: [(18)F]Fluciclatide PET imaging was well tolerated and demonstrated favorable characteristics for imaging αvß3 and αvß5 expression in melanoma and RCC. Higher uptake was observed in chromophobe than in nonchromophobe RCC. [(18)F]Fluciclatide may be a useful radiotracer to improve knowledge of integrin expression.

Molecular Neuroimaging of the Dopamine Transporter as a Patient Enrichment Biomarker for Clinical Trials for Early Parkinson's Disease.

The Critical Path for Parkinson's (CPP) Imaging Biomarker and Modeling and Simulation working groups aimed to achieve qualification opinion by the European Medicines Agency (EMA) Committee for Medical Products for Human Use (CHMP) for the use of baseline dopamine transporter neuroimaging for patient selection in early Parkinson's disease clinical trials. This paper describes the regulatory science strategy to achieve this goal. CPP is an international consortium of three Parkinson's charities and nine pharmaceutical partners, coordinated by the Critical Path Institute.

The Qualification of an Enrichment Biomarker for Clinical Trials Targeting Early Stages of Parkinson's Disease.

As therapeutic trials target early stages of Parkinson's disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Members of the Critical Path for Parkinson's Consortium formally submitted documentation to the European Medicines Agency (EMA) supporting the use of Dopamine Transporter (DAT) neuroimaging in early PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability. The research plan included longitudinal analysis of the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) and the Parkinson's Progression Markers Initiative (PPMI) study to estimate the degree of enrichment achieved and impact on future trials in subjects with early motor PD. The presence of reduced striatal DAT binding based on visual reads of single photon emission tomography (SPECT) scans in early motor PD subjects was an independent predictor of faster decline in UPDRS Parts II and III as compared to subjects with scans without evidence of dopaminergic deficit (SWEDD) over 24 months. The EMA issued in 2018 a full Qualification Opinion for the use of DAT as an enrichment biomarker in PD trials targeting subjects with early motor symptoms. Exclusion of SWEDD subjects in future clinical trials targeting early motor PD subjects aims to enrich clinical trial populations with idiopathic PD patients, improve statistical power, and exclude subjects who are unlikely to progress clinically from being exposed to novel test therapeutics.