10539 Background: Genomic analyses can identify actionable mutations in a subset of childhood cancers. However it has been challenging to translate actionable mutations into substantial benefits for adult cancers despite high mutation frequency. Methods: To test whether we could enhance identification of personalised therapies for high risk (HR) childhood cancers we conducted a pilot study (TARGET) evaluating a novel, comprehensive precision medicine platform incorporating molecular profiling, in vitro and in vivo drug testing. Results: We evaluated the first 29 patients with HR cancer (expected survival < 30%) enrolled prospectively over 15 months. Samples were collected from 15 CNS tumors, 10 solid tumors and 4 leukemias. All samples underwent targeted DNA sequencing. Pathogenic or likely pathogenic mutations were found in 59% (17/29) of tumors. 41% (12/29) had potentially actionable mutations. RNA-sequencing was performed on 27 samples. Previously described fusions were identified in 19% (5/27; 1 targetable, 1 clinical relevant and 3 diagnostic fusions). 37% (10/27) of samples also had actionable aberrations related to copy number changes or RNA expression. In vitro culture and establishment of patient-derived xenograft (PDX) were attempted in 19 and 21 fresh samples, respectively. The success rate of establishing a primary culture was 42% (8/19) and PDX engraftment rate was 67% (14/21). At least 1 drug hit was identified in 5 (56%) of the 9 samples screened using a high throughput drug screen of up to 165 compounds. Drug testing has been completed in 4 PDXs and was informative in all 4 cases allowing prioritisation of treatment recommendations. Genomic analysis in combination with RNA-seq, in vitro drug screening and PDX drug testing enriched the analysis and increased the ability to make personalised treatment recommendations from 41% (targeted panel alone) to 66%. Conclusions: This pilot study demonstrates that this novel, comprehensive platform is feasible and has the potential to improve outcome for HR childhood cancers. A multicentre study testing the implementation of the platform on a national level (PRISM trial) will open for Australian children with HR cancer under the Zero Childhood Cancer Program in 2017.