Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors.

Inhibition of heat shock 90 (Hsp90) molecular chaperones allows targeting of multiple proteins involved in tumorigenesis. We investigated the safety, recommended phase 2 dose (RP2D), and pharmacokinetic and pharmacodynamic profile of onalespib (AT13387), a potent synthetic Hsp90 inhibitor, administered on days 1, 2, 8, 9, 15, and 16 of 28 day cycles (QDx2/week) in a phase I trial. This study followed an accelerated titration design with a starting dose of 20 mg/m(2)/dose and a standard 3 + 3 dose escalation design for dose level 4 (120 mg/m(2)/dose) and above. Additional patients were enrolled at the RP2D with mandatory paired tumor biopsies to assess modulation of 210 client proteins using reverse phase protein array analysis. Thirty-one patients were treated; RP2D was established at 160 mg/m(2)/dose on the QDx2/week schedule. Common toxicities were gastrointestinal, hepatic, and hematologic. Pharmacokinetic profile was linear and plasma levels increased proportionally with dose (T½ ~8 h). No responses were observed; eight patients had stable disease for > 2 cycles with one patient remaining on study for 6 cycles. Target engagement was demonstrated by transcriptional upregulation of Hsp70 and Hsp27 in PBMCs. Statistically significant modulation of client proteins was not achieved in the 9 paired tumor biopsies evaluated; however, hierarchical clustering revealed two subgroups of patients with differential patterns of protein expression. Further combination studies are needed in order to target prospective driver oncoproteins.

Telephone technical support: an essential adjunct to a computer intervention for rural chronically ill women.

The purposes of this article are to describe the telephone technical support system used in the Women to Women support and health education computer outreach project for chronically ill rural women, discuss the preparation and role of the information systems specialist, and examine the nature and quality of telephone support requested and received. Telephone support records were tallied and categorized to determine the number of participants requiring assistance and the nature of problems described. The quality of telephone support received was assessed through a postintervention mail survey. About one third of participants sought telephone support, most frequently for problems related to impaired Internet service provider delivery and the university's Web-application platform. The quality of telephone support was rated highly by 96% of respondents. It was concluded that telephone technical support is a useful adjunct to a computer-based intervention and that quality support can be provided by including a competent information systems specialist on the research team.