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.
Invest New Drugs
; 33(4): 921-30, 2015 Aug.
Article
en En
| MEDLINE
| ID: mdl-26082332
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Benzamidas
/
Proteínas HSP90 de Choque Térmico
/
Isoindoles
/
Neoplasias
Límite:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Invest New Drugs
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos