First-in-human phase 1/1b study to evaluate sitravatinib in patients with advanced solid tumors.

Sitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient selection. In phase 1, 32 patients received 10-200 mg, while phase 1b dose expansion comprised 161 patients (150 mg n = 99, 120 mg n = 62). Maximum tolerated dose was determined as 150 mg daily. Dose-limiting toxicity was reported in 4/28 evaluable phase 1 patients (three at 200 mg, one at 80 mg). In phase 1b, 120 mg was defined as the recommended dose due to tolerability. Treatment-related adverse events (TRAEs) were experienced by 174/193 patients (90.2%); grade ≥ 3 TRAEs in 103 patients (53.4%). Most common TRAEs were diarrhea, fatigue, hypertension and nausea; TRAEs led to treatment discontinuation in 26 patients (13.5%) and death in one patient. Sitravatinib was steadily absorbed and declined from plasma with a terminal elimination half-life of 42.1-51.5 h following oral administration. Overall objective response rate was 11.8% in phase 1b, 13.2% in patients with non-small cell lung cancer (NSCLC) and 4.2% in patients with NSCLC with prior checkpoint inhibitor experience. Sitravatinib demonstrated manageable safety and modest clinical activity in solid tumors. NCT02219711 (first posted August 14, 2014).

MosquitoMap and the Mal-area calculator: new web tools to relate mosquito species distribution with vector borne disease.

BACKGROUND: Mosquitoes are important vectors of diseases but, in spite of various mosquito faunistic surveys globally, there is a need for a spatial online database of mosquito collection data and distribution summaries. Such a resource could provide entomologists with the results of previous mosquito surveys, and vector disease control workers, preventative medicine practitioners, and health planners with information relating mosquito distribution to vector-borne disease risk. RESULTS: A web application called MosquitoMap was constructed comprising mosquito collection point data stored in an ArcGIS 9.3 Server/SQL geodatabase that includes administrative area and vector species x country lookup tables. In addition to the layer containing mosquito collection points, other map layers were made available including environmental, and vector and pathogen/disease distribution layers. An application within MosquitoMap called the Mal-area calculator (MAC) was constructed to quantify the area of overlap, for any area of interest, of vector, human, and disease distribution models. Data standards for mosquito records were developed for MosquitoMap. CONCLUSION: MosquitoMap is a public domain web resource that maps and compares georeferenced mosquito collection points to other spatial information, in a geographical information system setting. The MAC quantifies the Mal-area, i.e. the area where it is theoretically possible for vector-borne disease transmission to occur, thus providing a useful decision tool where other disease information is limited. The Mal-area approach emphasizes the independent but cumulative contribution to disease risk of the vector species predicted present. MosquitoMap adds value to, and makes accessible, the results of past collecting efforts, as well as providing a template for other arthropod spatial databases.