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

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

Rinistachya hilleri gen. et sp. nov.(Sphenophyllales), from the upper Devonian of South Africa

A rich and diverse plant assemblage has been excavated from latest Devonian (Famennian) black shales of the Witpoort Formation (Witteberg Group) at Waterloo Farm, close to the city of Grahamstown (South Africa). Several specimens of a new sphenopsid have been collected. The description of this as a new taxon, here named Rinistachya hilleri, gen. et sp. nov., provides an important addition to the scarce early record of the group. Rinistachya hilleri presents a novel architecture that include apparently plesiomorphic characters, reminiscent of the organisation of the Iridopteridales (including the production of two types of laterals at one node, the location of fertile parts in loose whorls on lateral branches and an organisation of the fertile parts in which they branch several times before bearing distally elongate sporangia). Other characters unambiguously nest Rinistachya within the Sphenopsida (including presence of planate and slightly webbed ultimate appendages and lateral strobili made of successive whorls of fertile leaves with fertile parts located at their axil). This provides strong support for a close relationship between Sphenopsida and Iridopteridales. Rinistachya furthermore represents the first record of a Devonian sphenopsid from Gondwana and extends the known distribution of the Sphenopsida from the tropics to very high palaeolatitudes. It is a new sphenopsid with a peculiar organisation. The new taxon allows better characterization of the initial evolutionary radiation at the base of the group