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

Romain Coriat,1 Sandrine J Faivre,2 Olivier Mir,3 Chantal Dreyer,2 Stanislas Ropert,3 Mohammed Bouattour,2 Robert Desjardins,4 François Goldwasser,3 Eric Raymond5 1Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris...

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Autores principales:	Coriat R, Faivre SJ, Mir O, Dreyer C, Ropert S, Bouattour M, Desjardins R, Goldwasser F, Raymond E
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2016
Materias:	Phase I topoisomerase I inhibitor Irinotecan Fluorescence HPLC. Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/16301eb3461a4e89964b273d5105eb1f
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spelling	oai:doaj.org-article:16301eb3461a4e89964b273d5105eb1f2021-12-02T03:58:28ZPharmacokinetics 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 study1178-2013https://doaj.org/article/16301eb3461a4e89964b273d5105eb1f2016-11-01T00:00:00Zhttps://www.dovepress.com/pharmacokinetics-and-safety-of-dts-108-a-human-oligopeptide-bound-to-s-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Romain Coriat,1 Sandrine J Faivre,2 Olivier Mir,3 Chantal Dreyer,2 Stanislas Ropert,3 Mohammed Bouattour,2 Robert Desjardins,4 François Goldwasser,3 Eric Raymond5 1Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris, 2Department of Medical Oncology, Beaujon Teaching Hospital, Université Paris Diderot, Paris 7, Clichy, 3Department of Medical Oncology, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris, France; 4Drais Pharmaceuticals, Bridgewater, NJ, USA; 5Groupe Hospitalier Paris Saint-Joseph, Paris, France 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. Conclusion: 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/m2 every 2 weeks in patients with advanced/metastatic solid tumors. Keywords: Phase I, topoisomerase I inhibitor, irinotecan, fluorescence HPLCCoriat RFaivre SJMir ODreyer CRopert SBouattour MDesjardins RGoldwasser FRaymond EDove Medical PressarticlePhase Itopoisomerase I inhibitorIrinotecanFluorescence HPLC.Medicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 11, Pp 6207-6216 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Phase I topoisomerase I inhibitor Irinotecan Fluorescence HPLC. Medicine (General) R5-920
spellingShingle	Phase I topoisomerase I inhibitor Irinotecan Fluorescence HPLC. Medicine (General) R5-920 Coriat R Faivre SJ Mir O Dreyer C Ropert S Bouattour M Desjardins R Goldwasser F Raymond E 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
description	Romain Coriat,1 Sandrine J Faivre,2 Olivier Mir,3 Chantal Dreyer,2 Stanislas Ropert,3 Mohammed Bouattour,2 Robert Desjardins,4 François Goldwasser,3 Eric Raymond5 1Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris, 2Department of Medical Oncology, Beaujon Teaching Hospital, Université Paris Diderot, Paris 7, Clichy, 3Department of Medical Oncology, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris, France; 4Drais Pharmaceuticals, Bridgewater, NJ, USA; 5Groupe Hospitalier Paris Saint-Joseph, Paris, France 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. Conclusion: 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/m2 every 2 weeks in patients with advanced/metastatic solid tumors. Keywords: Phase I, topoisomerase I inhibitor, irinotecan, fluorescence HPLC
format	article
author	Coriat R Faivre SJ Mir O Dreyer C Ropert S Bouattour M Desjardins R Goldwasser F Raymond E
author_facet	Coriat R Faivre SJ Mir O Dreyer C Ropert S Bouattour M Desjardins R Goldwasser F Raymond E
author_sort	Coriat R
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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	Dove Medical Press
publishDate	2016
url	https://doaj.org/article/16301eb3461a4e89964b273d5105eb1f
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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

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