Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients.

BACKGROUND: This phase I first-in-human study was conducted in Japanese patients to investigate the safety, pharmacokinetics (PKs), and determine the maximum tolerated dose (MTD) of oral TAK-285, a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2. METHODS: The TAK-285 dose was escalated until MTD was determined. A second patient cohort received TAK-285 at the MTD for at least 4 weeks. RESULTS: In all, 26 patients received TAK-285 at doses ranging from 50 to 400 mg once daily (q.d.) or twice daily (b.i.d.); 20 patients made up the dose escalation cohort and the remaining 6 patients were the repeated administration cohort. TAK-285 was well tolerated. Dose-limiting toxicities noted in two patients who received 400 mg b.i.d. were grade 3 increases in aminotransferases and grade 3 decreased appetite. Consequently, the MTD was determined to be 300 mg b.i.d. Absorption of TAK-285 was rapid after oral dosing, and plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. A partial response was observed for one patient with parotid cancer who received 300 mg b.i.d. CONCLUSION: The toxicity profile and PK properties of oral TAK-285 warrant further evaluation.

Structural determination of a new mutagenic heterocyclic amine, 2-amino-1,7,9-trimethylimidazo[4,5-g]quinoxaline (7,9-DiMeIgQx), present in beef extract.

We previously found two new mutagens, compounds I and II, in bacteriological-grade beef extract by monitoring the mutagenicity to a new Salmonella strain, YG1024; compound I was identified as 2-amino-4-hydroxymethyl-3,8-dimethylimidazo[4,5-f]quinoxaline (4-CH2OH-8-MeIQx). In the present study, we isolated compound II from the beef extract, which accounted for 2% of the total mutagenicity of materials adsorbed on blue cotton. Further, we found that a large quantity of compound II was produced by heating a mixture of creatine, threonine and glucose (1:1:0.5) at 200 degrees C for 5 h, the level being 860-fold of that in the beef extract. The structure of this compound was determined to be 2-amino-1,7,9-trimethylimidazo[4,5-g]quinoxaline (7,9-DiMeIgQx) by X-ray crystallography. The amount of 7,9-DiMeIgQx in bacteriological-grade beef extract was estimated to be 53 ng/g. This compound induced 13 800 and 670 revertants of S. typhimurium YG1024 and TA98 respectively, per micrograms in the presence of S9 mix.

Isolation and identification of a new mutagen, 2-amino-4-hydroxy-methyl-3,8-dimethylimidazo[4,5-f]quinoxaline (4-CH2OH-8-MeIQx), from beef extract.

By monitoring the mutagenicity to a new Salmonella tester strain, YG1024, which has a much higher level of O-acetyltransferase activity than S.typhimurium TA98, we found two new mutagenic compounds in bacteriological-grade beef extract. One of them (compound I), which had a similar UV spectrum to that of 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), was isolated and shown to account for approximately 2% of the total mutagenicity of the materials adsorbed to blue cotton, and its concentration was estimated to be 6.0 ng/g beef extract. This amount of compound in beef extract was insufficient to allow measurements of various spectra, but its level was increased approximately 9-fold by heating beef extract with creatine and threonine at 200 degrees C for 5 h. From UV and mass spectra of the compound obtained from beef extract heated with creatine plus threonine, it was deduced to be a hydroxymethyl derivative of aminodimethylimidazo-quinoxaline. Compound I was isolated from the urine of rats given 4,8-DiMeIQx and identified as 2-amino-4-hydroxymethyl-3,8-dimethylimidazo[4,5-f]quinoxaline (4-CH2OH-8-MeIQx) by 1H-NMR analysis. 4-CH2OH-8-MeIQx induced 326,000 revertants of YG1024 and 99,000 revertants of TA98 per micrograms in the presence of S9 mix.