title: Pharmacokinetics and safety of DTS-108, a human oligopeptide bound to SN-38 with an esterase-sensitive cross-linker in patients with advanced malignancies: a Phase I study.
abstract: BACKGROUND
  DTS-108 is a hydrosoluble prodrug, where the SN-38 moiety is covalently linked to a 20-amino acid vector peptide by a specific esterase-sensitive cross-linker, releasing 7-ethyl-10-hydroxycampthotecin (SN-38) by esterase bond cleavage.
  
  
  METHODS
  The pharmacokinetics of DTS-108, adverse events graded according to NCI-CTCv3.1, dose-limiting toxicities at cycle 1, the maximum tolerated dose (MTD), and the recommended Phase II dose (RP2D) of intravenous DTS-108 (1-2 hours) every 2 weeks were evaluated in a first-in-human Phase I study in patients with advanced/metastatic carcinomas, according to an accelerated dose escalation design. SN-38 and SN-38 glucuronide (SN-38G) levels were evaluated with fluorescence high-performance liquid chromatography (HPLC) test, then liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods.
  
  
  RESULTS
  Forty-two patients received DTS-108 across 14 dosing cohorts (range 3-416 mg/m2). At 416 mg/m2, three out of six patients had grade 4 neutropenia thereby defining the MTD and the RP2D at 313 mg/m2. Fluorescence HPLC was inaccurate to quantify DTS-108 and its metabolites (SN-38 and SN-38G). New processes and analytical LC/MS/MS methods for testing SN-38 were implemented. At a dose of 313 mg/m2, mean DTS-108, SN-38, and SN-38G area under the plasma concentration-time curve to infinity (coefficients of variation %) were 439,293 (24%), 1,992 (34%), and 4,538 (46%) h·ng/mL. Stable disease (according to Response Evaluation Criteria in Solid Tumors) was observed in nine patients.
  
  
  CONCLUSIONS
  Assessing SN-38 concentration using fluorescence HPLC is questionable since this method failed to monitor dose escalation of DTS-108, a new topoisomerase I inhibitor, due to ex vivo degradation. LC/MS/MS methods were consistent in evaluating SN-38 exposures allowing drug monitoring. The maximum tolerated dose of DTS-108 was 416 mg/m2. The RP2D for intravenous DTS-108 was 313 mg/m2every 2 weeks in patients with advanced/metastatic solid tumors.
authors.affiliation: Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris.
authors.forename: Romain
authors.initials: R
authors.lastname: Coriat
authors.affiliation: Department of Medical Oncology, Beaujon Teaching Hospital, Université Paris Diderot, Paris 7, Clichy.
authors.forename: Sandrine J
authors.initials: SJ
authors.lastname: Faivre
authors.affiliation: Department of Medical Oncology, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Mir
authors.affiliation: Department of Medical Oncology, Beaujon Teaching Hospital, Université Paris Diderot, Paris 7, Clichy.
authors.forename: Chantal
authors.initials: C
authors.lastname: Dreyer
authors.affiliation: Department of Medical Oncology, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Ropert
authors.affiliation: Department of Medical Oncology, Beaujon Teaching Hospital, Université Paris Diderot, Paris 7, Clichy.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Bouattour
authors.affiliation: Drais Pharmaceuticals, Bridgewater, NJ, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Desjardins
authors.affiliation: Department of Medical Oncology, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Goldwasser
authors.affiliation: Groupe Hospitalier Paris Saint-Joseph, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D020719:Glucuronides / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000972:Antineoplastic Agents, Phytogenic; C529642:DTS-108; D020719:Glucuronides; D010455:Peptides; D002166:Camptothecin
keywords: Phase I; fluorescence HPLC; irinotecan; topoisomerase I inhibitor