title: 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.
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.
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg 31, Rm 3A44, Bethesda, MD, 20892, USA.
authors.forename: Khanh
authors.initials: K
authors.lastname: Do
authors.forename: Giovanna
authors.initials: G
authors.lastname: Speranza
authors.forename: Lun-Ching
authors.initials: LC
authors.lastname: Chang
authors.forename: Eric C
authors.initials: EC
authors.lastname: Polley
authors.forename: Rachel
authors.initials: R
authors.lastname: Bishop
authors.forename: Weimin
authors.initials: W
authors.lastname: Zhu
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.forename: Sunmin
authors.initials: S
authors.lastname: Lee
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kinders
authors.forename: Larry
authors.initials: L
authors.lastname: Phillips
authors.forename: Jerry
authors.initials: J
authors.lastname: Collins
authors.forename: John
authors.initials: J
authors.lastname: Lyons
authors.forename: Woondong
authors.initials: W
authors.lastname: Jeong
authors.forename: Ramya
authors.initials: R
authors.lastname: Antony
authors.forename: Alice P
authors.initials: AP
authors.lastname: Chen
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006360:Heat-Shock Proteins; D006801:Humans; D054833:Isoindoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018832:Molecular Chaperones; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D001549:Benzamides; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D054833:Isoindoles; D018832:Molecular Chaperones; D012333:RNA, Messenger; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone