Phase 1 dose-escalation, pharmacokinetic, and cerebrospinal fluid distribution study of TAK-285, an investigational inhibitor of EGFR and HER2

Abstract

SummaryIntroduction 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.

Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors

“…We have focused our development on chiral benzylamine based pyrrolo [2,3-d]pyrimidines as EGFR inhibitors [19][20][21]. Only three pyrroloyrimidines based EGFR inhibitors have reached clinical trials, namely PKI-166 [22], AEE-788 [23,24], and TAK-285 [25,26], see Figure 1. Our lead compound I [20] (Figure 1), which possessed high in vitro enzymatic and cellular activity, was unfortunately a substrate of the breast cancer resistant protein and the Pglycoprotein ABC-transporters, making further development challenging [21].…”

Pyrrolopyrimidine: A Versatile Scaffold for Construction of Targeted Anti-cancer Agents

“…Only three pyrroloyrimidine based EGFR inhibitors have reached clinical trials, namely PKI-166(Compound 33) 111 , AEE-788 (Compound 34) 112,113 , and TAK-285 (Compound 35) 114,115 .…”

Pyrrolopyrimidine, A Multifaceted Scaffold in Cancer Targeted Therapy

“…The membrane bound epidermal growth factor receptor tyrosine kinase (EGFR) has been one of the most investigated kinases, since EGFR amplification or mutation has been noted in various cancer types. Only three pyrrolopyrimidine based EGFR inhibitors have reached clinical trials, namely PKI-166 (cpd 33)[107], AEE-788 (cpd 34)[108,109], and TAK-285 (cpd 35)[110,111].…”