title: First-in-human phase I dose escalation study of a second-generation non-ansamycin HSP90 inhibitor, AT13387, in patients with advanced solid tumors.
abstract: OBJECTIVE
  AT13387 is a potent second-generation, fragment-derived HSP90 inhibitor. This phase I study investigated the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and safety, pharmacokinetic, and pharmacodynamic profiles of two AT13387 regimens in a refractory solid tumor population.
  
  
  METHODS
  Standard 3+3 dose escalation was used. MTD and RP2D determinations were based on the occurrence of dose-limiting toxicities (DLT) and overall toxicity, respectively. Pharmacokinetic parameters were measured after single and multiple doses. AT13387-mediated induction of HSP70 was evaluated in plasma, peripheral blood mononuclear cells, and paired tumor biopsies.
  
  
  RESULTS
  Sixty-two patients were treated with doses ranging from 10 to 120 mg/m(2) twice weekly and 150 to 310 mg/m(2) once weekly (both for 3 weeks every 28 days). One DLT of visual disturbance occurred at 120 mg/m(2), which was considered the MTD and RP2D for the twice-weekly regimen. No formal DLTs occurred in the once-weekly regimen, but multiple moderately severe toxicities, including diarrhea, nausea, vomiting, fatigue, and systemic infusion reactions, led to selection of 260 mg/m(2) as the RP2D. Exposures of AT13387 increased proportionally with dose. Target engagement as measured by HSP70 induction occurred in plasma and tumor biopsy samples. One patient with gastrointestinal stromal tumor (GIST) who had progressive disease on imatinib had a partial response and remained on treatment for 10 months. Twenty-one patients (34%) had stable disease, which lasted >120 days in 7 patients.
  
  
  CONCLUSIONS
  AT13387 administered once or twice weekly has an acceptable safety profile and demonstrated evidence of target engagement and preliminary antitumor activity.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. geoffrey_shapiro@dfciharvard.edu dmahadevan@WESTCLINIC.com.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts. Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Eunice
authors.initials: E
authors.lastname: Kwak
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Beth Israel Deaconess Medical School, Boston, Massachusetts.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Dezube
authors.affiliation: Astex Pharmaceuticals, Inc., Dublin, California.
authors.forename: Murray
authors.initials: M
authors.lastname: Yule
authors.affiliation: Astex Pharmaceuticals, Inc., Dublin, California.
authors.forename: John
authors.initials: J
authors.lastname: Ayrton
authors.affiliation: Astex Pharmaceuticals, Inc., Dublin, California.
authors.forename: John
authors.initials: J
authors.lastname: Lyons
authors.affiliation: Arizona Cancer Center, Tuscon, Arizona. geoffrey_shapiro@dfciharvard.edu dmahadevan@WESTCLINIC.com.
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D054833:Isoindoles / Q000008:administration & dosage* / Q000009:adverse effects; D007963:Leukocytes, Mononuclear; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone