title: A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies.
abstract: BACKGROUND
  Heat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included characterisation of the safety profile, pharmacokinetics (PKs) and pharmacodynamics (PDs).
  
  
  METHODS
  Heat-shock protein 990 was administered orally once or two times weekly on a 28-day cycle schedule in patients with advanced solid tumours. Dose escalation was guided by a Bayesian logistic regression model with overdose control.
  
  
  RESULTS
  A total of 64 patients were enrolled. Fifty-three patients received HSP990 once weekly at 2.5, 5, 10, 20, 30, 50 or 60 mg, whereas 11 patients received HSP990 two times weekly at 25 mg. Median duration of exposure was 8 weeks (range 1-116 weeks) and 12 patients remained on treatment for >16 weeks. Dose-limiting toxicities occurred in seven patients and included diarrhoea, QTc prolongation, ALT/AST elevations and central neurological toxicities. The most common drug-related adverse events were diarrhoea, fatigue and decreased appetite. Further dose escalation beyond 60 mg once weekly was not possible owing to neurological toxicity. Rapid absorption, no drug accumulation and large interpatient variability in PK exposures were observed. No objective responses were seen; 25 patients had a best overall response of stable disease.
  
  
  CONCLUSIONS
  Heat-shock protein 990 is relatively well tolerated, with neurological toxicity being the most relevant DLT. The single agent MTD/RP2D of HSP990 was declared at 50 mg once weekly.
authors.affiliation: Drug Development Program, UHN - Princess Margaret Cancer Centre, Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Spreafico
authors.affiliation: Institut Claudius Regaud, Toulouse, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Delord
authors.affiliation: Vall d'Hebron University Hospital, Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: De Mattos-Arruda
authors.affiliation: Institut Claudius Regaud, Toulouse, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Berge
authors.affiliation: Vall d'Hebron University Hospital, Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Rodon
authors.affiliation: Institut Claudius Regaud, Toulouse, France.
authors.forename: E
authors.initials: E
authors.lastname: Cottura
authors.affiliation: Drug Development Program, UHN - Princess Margaret Cancer Centre, Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: P L
authors.initials: PL
authors.lastname: Bedard
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Akimov
authors.affiliation: Novartis Pharmaceuticals Corp, East Hanover, NJ, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lu
authors.affiliation: Novartis Pharmaceuticals Corp, East Hanover, NJ, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pain
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Kaag
authors.affiliation: Drug Development Program, UHN - Princess Margaret Cancer Centre, Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: L L
authors.initials: LL
authors.lastname: Siu
authors.affiliation: Vall d'Hebron University Hospital, Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cortes
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D050888:Heat-Shock Proteins, Small / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: C570862:2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D050888:Heat-Shock Proteins, Small; D011728:Pyridones; D011743:Pyrimidines