title: Debio0932, a second-generation oral heat shock protein (HSP) inhibitor, in patients with advanced cancer-results of a first-in-man dose-escalation study with a fixed-dose extension phase.
abstract: BACKGROUND
  Objective was to determine maximum tolerated dose (MTD), recommended dose (RD) and schedule, safety, pharmacokinetic (PK) profile, pharmacodynamic (PD) effects, and antitumor activity of Debio0932, a new second-generation oral heat shock protein (HSP) inhibitor.
  
  
  METHODS
  This was a multicenter, uncontrolled, open-label, nonrandomized, dose-escalation study in adults with treatment-resistant advanced cancer. Groups of three patients received oral Debio0932 either daily or every other day. The starting dose of 50 mg was escalated until the MTD was reached, i.e. dose-limiting toxicity (DLT) occurred in ≥2 patients. Further 9 patients and an extension cohort of 30 patients were treated at the next lower dose (=RD). Adverse events (AEs), tumor response, PK, and HSP70 levels in peripheral blood mononuclear cells were recorded over 30 days.
  
  
  RESULTS
  Fifty patients were treated with doses up to 1600 mg, at which level three DLT occurred (febrile neutropenia, diarrhea, asthenia). In total, 39 patients were then treated at the RD of 1000 mg daily. Most common drug-related AEs were asthenia and gastrointestinal events. No ocular toxicities were observed. Debio0932 was rapidly absorbed and metabolized. Plasma steady state was reached within 9 days. Volume of distribution was high and elimination half-life was 9-11 h. Food had no effect on PK. PD showed large interpatient variability, but no dose-effect relationship. Partial tumor response was observed in 2 patients (NSCLC and breast cancer), stable disease (SD) in 12 patients (5 of 8 NSCLC patients). In the extension cohort, 9 patients had SD, and 1 patient a partial metabolic tumor response.
  
  
  CONCLUSIONS
  Debio0932 has limited clinical activity, together with manageable toxicity. Further development as adjunct treatment of NSCLC at daily doses of 1000 mg is warranted.
  
  
  BACKGROUND
  NCT01168752.
authors: Department of Medical Oncology, Centre Georges François Leclerc, Dijon.
authors: N
authors: N
authors: Isambert
authors: Oncology and Clinical Research Unit, Institut Claudius Regaud, Toulouse.
authors: J-P
authors: JP
authors: Delord
authors: Drug Development Department (DITEP), Gustave Roussy Cancer Campus and University Paris-Sud, Paris, France.
authors: J-C
authors: JC
authors: Soria
authors: Drug Development Department (DITEP), Gustave Roussy Cancer Campus and University Paris-Sud, Paris, France.
authors: A
authors: A
authors: Hollebecque
authors: Oncology and Clinical Research Unit, Institut Claudius Regaud, Toulouse.
authors: C
authors: C
authors: Gomez-Roca
authors: Debiopharm International SA, Lausanne, Switzerland.
authors: D
authors: D
authors: Purcea
authors: Debiopharm International SA, Lausanne, Switzerland.
authors: E
authors: E
authors: Rouits
authors: Debiopharm International SA, Lausanne, Switzerland.
authors: R
authors: R
authors: Belli
authors: Department of Medical Oncology, Centre Georges François Leclerc, Dijon. Electronic address: pfumoleau@cgfl.fr.
authors: P
authors: P
authors: Fumoleau
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D052117:Benzodioxoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001711:Biotransformation; D054796:Drug Dosage Calculations; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D065228:Non-Randomized Controlled Trials as Topic; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; C543177:CUDC 305; D018841:HSP90 Heat-Shock Proteins; D007093:Imidazoles
keywords: Debio0932; NSCLC; heat shock protein; pharmacokinetic