serum and via radiology. PD was tested using Axin2 mRNA levels in hair follicles (HFs). Immune markers were analysed in pre-and post-dose biopsies. Dose escalation and DLT incidence assessment were assisted by a Bayesian approach, with a DLT period of 28d. Results: As of April 2018, 5 pts were treated at 16 mg and 3 at 24 mg. 50% were female, median age (range) 55.5 yr (47-71). There was one DLT (grade 2 dysgeusia). Adverse events (>20%) were: dysgeusia (62%), fatigue (37%), weight loss (37%), back pain (37%), headache (37%), vomiting (25%), nausea (25%) and abdominal pain (25%). At the dose of 16 mg ETC-159 showed inter-patient PK variability, with a mean t 1 =2 of 15h (d1) and 37h (d15). Serum b-CTX reduction from pre-dose was seen in 6/8 pts. In 1 pt serum b-CTX increased to > 1000 pg/mL (with reduction of bone mineral density) and reduced after ETC-159 discontinuation; in 1 pt b-CTX was not assessed due to early discontinuation. 4 pts withdrew for progressive disease,1 pt for DLT, 1pt for consent withdrawal and 2 pts are ongoing. Decreased Axin2 mRNA was seen in HFs and a 2-fold increase of the ratio of tumour infiltrating CD8 þ /FOXP3 þ T-cells was seen in the tumour. Conclusions: ETC-159 with prophylactic denosumab is safe; there are no compression fractures and b-CTX decreases in most pts. ETC-159 has PD activity and increases immune infiltration. ETC-159 dosing is ongoing at 24 mg. Clinical trial identification: NCT02521844.

BackgroundThe design and synthesis of hybrid molecules will explore finding new drugs.ObjectivesThe synthesized hybrid molecules to evaluate their biological properties.MethodsApply click chemistry to tether flavonols and benzenesulfonamide.ResultsTwo drug candidates show potential against lung cancer.ConclusionsTwo drug candidates did not affect the normal cells and provided a new drug design route.

viral DNA are other key targets with clinical relevance. We report here the enhancement of an ultra-sensitive sequencing platform technology (AmpliMARK) for the simultaneous detection of multiple classes of genomic alterations in liquid biopsies, extending to common cancers such as breast, colorectal, lung and nasopharyngeal cancers (NPC). Methods: A primer-based target capture panel covering 50 genes, 6 microsatellite loci and 2 viral targets was validated using biologically relevant reference materials and clinical samples (cfDNA) from breast, lung, colorectal and NPC (n ¼ 117). Orthogonal validation was done with PCR-based EGFR detection, EBV BamHI-W CpG DNA, and MSI fragment analysis, and to matched tumor tissue where available (n ¼ 65). Results: The lower limits of detection (LOD) for variant alleles, MSI, viral DNA and CNVs were 0.1%, 5%, 50 IU/mL and 1.5-fold, respectively. Concordance with PCRbased detection of EGFR mutations was high with 100% PPV and 95.2% NPV. Cancerassociated viral DNA detection by AmpliMARK had 89% concordance with PCR in NPC. For MSI detection in cfDNA, PPV was 100% with NPV of 93.5% compared to tissue-based testing. For EGFR, KRAS and BRAF mutations, matched tissue testing had a combined 100% PPV and 65% NPV. CNVs were detected in cfDNA from 5 of 9 known ERBB2 (HER2)-amplified breast cancer cases. ALK, MET, EGFR CNVs ranging from 1.89-to 35-fold were also confirmed in lung cancer samples including in pleural effusion and cerebrospinal fluid. Among lung cancer cases with no EGFR mutations, BRAF, NRAS, MET exon 14 skipping, ERBB2 exon 20 insertion (n ¼ 1 each) and KRAS (n ¼ 6) were confirmed by the platform. Structural rearrangements resulting in fusion products of ALK, ROS1 and RET were detectable by the platform in reference material. Conclusions: We report the enhancement of a technology platform for comprehensive genomic profiling of liquid biopsies. Excellent concordance to standard methods and tissue results is demonstrated. Legal entity responsible for the study: Lucence Diagnostics Pte. Ltd.