title: First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma.
abstract: BACKGROUND
  DT01 is a DNA-repair inhibitor preventing recruitment of DNA-repair enzymes at damage sites. Safety, pharmacokinetics and preliminary efficacy through intratumoural and peritumoural injections of DT01 were evaluated in combination with radiotherapy in a first-in-human phase I trial in patients with unresectable skin metastases from melanoma.
  
  
  METHODS
  Twenty-three patients were included and received radiotherapy (30 Gy in 10 sessions) on all selected tumour lesions, comprising of two lesions injected with DT01 three times a week during the 2 weeks of radiotherapy. DT01 dose levels of 16, 32, 48, 64 and 96 mg were used, in a 3+3 dose escalation design, with an expansion cohort at 96 mg.
  
  
  RESULTS
  The median follow-up was 180 days. All patients were evaluable for safety and pharmacokinetics. No dose-limiting toxicity was observed and the maximum-tolerated dose was not reached. Most frequent adverse events were reversible grades 1 and 2 injection site reactions. Pharmacokinetic analyses demonstrated a systemic passage of DT01. Twenty-one patients were evaluable for efficacy on 76 lesions. Objective response was observed in 45 lesions (59%), including 23 complete responses (30%).
  
  
  CONCLUSIONS
  Intratumoural and peritumoural DT01 in combination with radiotherapy is safe and pharmacokinetic analyses suggest a systemic passage of DT01.
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud 75005, France.|EA7285, Versailles-Saint-Quentin-en-Yvelines University, Versailles 78000, France.
authors.forename: C
authors.initials: C
authors.lastname: Le Tourneau
authors.affiliation: CHU de Nantes-Hôtel Dieu, Nantes 44093, France.
authors.forename: B
authors.initials: B
authors.lastname: Dreno
authors.affiliation: Radiotherapy Department, Institut Curie, Paris 75005, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Kirova
authors.affiliation: La Timone Hospital-APHM, Aix-Marseille University, Marseille 13385, France.
authors.forename: J J
authors.initials: JJ
authors.lastname: Grob
authors.affiliation: Dermatology department, Saint-André Hospital, CHU de Bordeaux, Bordeaux 33000, France.
authors.forename: T
authors.initials: T
authors.lastname: Jouary
authors.affiliation: Dermatology department, Saint-André Hospital, CHU de Bordeaux, Bordeaux 33000, France.
authors.forename: C
authors.initials: C
authors.lastname: Dutriaux
authors.affiliation: Lyon Sud Hospital Center, Lyon 1 University, Pierre Benite 69495, France.
authors.forename: L
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Saint-Louis Hospital, APHP, Paris 75010, France.
authors.forename: C
authors.initials: C
authors.lastname: Lebbé
authors.affiliation: Dermatology department, CHRU of Lille, Lille 59037, France.
authors.forename: L
authors.initials: L
authors.lastname: Mortier
authors.affiliation: Ambroise Paré Hospital, Boulogne Billancourt 92104, France.
authors.forename: P
authors.initials: P
authors.lastname: Saiag
authors.affiliation: Cochin hospital, APHP, Paris 75014, France.
authors.forename: M F
authors.initials: MF
authors.lastname: Avril
authors.affiliation: Bichat Hospital, Paris 75877, France.
authors.forename: E
authors.initials: E
authors.lastname: Maubec
authors.affiliation: CHU Rouen, Charles-Nicolle, Rouen 76000, France.
authors.forename: P
authors.initials: P
authors.lastname: Joly
authors.affiliation: Institut Curie, Paris 75005, France.
authors.forename: P
authors.initials: P
authors.lastname: Bey
authors.affiliation: Radiotherapy Department, Institut Curie, Paris 75005, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Cosset
authors.affiliation: DNA Therapeutics, Evry 91058, France.
authors.forename: J S
authors.initials: JS
authors.lastname: Sun
authors.affiliation: Department of Biostatistics, Institut Curie, Paris 75005, France.
authors.forename: B
authors.initials: B
authors.lastname: Asselain
authors.affiliation: DNA Therapeutics, Evry 91058, France.|Institut Curie, Orsay 91405, France.
authors.forename: F
authors.initials: F
authors.lastname: Devun
authors.affiliation: Saint-Louis Hospital, APHP, Paris 75010, France.
authors.forename: M E
authors.initials: ME
authors.lastname: Marty
authors.affiliation: Institut Curie, Orsay 91405, France.|CNRS-UMR3347, INSERM-U1021, Paris-Sud University, Orsay 91405, France.
authors.forename: M
authors.initials: M
authors.lastname: Dutreix
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D059248:Chemoradiotherapy; D002738:Chloroquine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002784:Cholesterol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004247:DNA / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000556:secondary* / Q000628:therapy; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016879:Salvage Therapy; D012878:Skin Neoplasms / Q000556:secondary* / Q000628:therapy; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; C000611563:DT01 compound; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; D002738:Chloroquine; D004247:DNA; D002784:Cholesterol