Phase 1 dose-escalation, pharmacokinetic, and cerebrospinal fluid distribution study of TAK-285, an investigational inhibitor of EGFR and HER2Report as inadecuate

Phase 1 dose-escalation, pharmacokinetic, and cerebrospinal fluid distribution study of TAK-285, an investigational inhibitor of EGFR and HER2 - Download this document for free, or read online. Document in PDF available to download.

Investigational New Drugs

, Volume 32, Issue 1, pp 160–170

First Online: 02 July 2013Received: 22 April 2013Accepted: 06 June 2013DOI: 10.1007-s10637-013-9988-x

Cite this article as: LoRusso, P., Venkatakrishnan, K., Chiorean, E.G. et al. Invest New Drugs 2014 32: 160. doi:10.1007-s10637-013-9988-xSummary

Introduction This phase 1 study assessed safety, maximum tolerated dose MTD, pharmacokinetics, cerebrospinal fluid CSF distribution, and preliminary clinical activity of the receptor tyrosine kinase inhibitor TAK-285. Methods Patients with advanced, histologically confirmed solid tumors and Eastern Cooperative Oncology Group performance status ≤2 received daily oral TAK-285; daily dose was escalated within defined cohorts until MTD and recommended phase 2 dose RP2D were determined. Eleven patients were enrolled into an RP2D cohort. Blood samples were collected from all cohorts; CSF was collected at pharmacokinetic steady-state from RP2D patients. Tumor responses were assessed every 8 weeks per Response Evaluation Criteria in Solid Tumors. Results Fifty-four patients were enrolled median age 60; range, 35–76 years. The most common diagnoses were cancers of the colon 28 %, breast 17 %, and pancreas 9 %. Escalation cohorts evaluated doses from 50 mg daily to 500 mg twice daily; the MTD-RP2D was 400 mg twice daily. Dose-limiting toxicities included diarrhea, hypokalemia, and fatigue. Drug absorption was fast median time of maximum concentration was 2–3 h, and mean half-life was 9 h. Steady-state average unbound CSF concentration geometric mean 1.54 range, 0.51–4.27 ng-mL; n = 5 at the RP2D was below the 50 % inhibitory concentration 9.3 ng-mL for inhibition of tyrosine kinase activity in cells expressing recombinant HER2. Best response was stable disease 12 weeks of nonprogression in 13 patients. Conclusions TAK-285 was generally well tolerated at the RP2D. Distribution in human CSF was confirmed, but the free concentration of the drug was below that associated with biologically relevant target inhibition.

KeywordsBreast cancer Brain metastases EGFR HER2 Pharmacokinetics Previous PublicationPortions of the data were presented at: Annual Meeting of the American Society of Clinical Oncology; June 3–7, 2011; Chicago, IL.

Abstract 2538 poster.

Trial RegistrationNCT00535522

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Author: Patricia LoRusso - Karthik Venkatakrishnan - E. Gabriela Chiorean - Dennis Noe - Jing-Tao Wu - Serap Sankoh - Maria Corvez


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