485P - Challenge in the pharmacokinetic evaluation of DTS-108, a new topoisomerase I inhibitor, in patients with advanced carcinomas

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Clinical research
Basic Scientific Principles
Presenter Olivier Mir
Authors O. Mir1, S. Faivre2, C. Dreyer3, R. Coriat4, M. Bouattour5, F. Goldwasser6, E. Raymond7
  • 1Oncology Department, Teaching Hospital Cochin, AP-HPUniversit, FR-75679 - Paris CEDEX 14/FR
  • 2Cancérologie (oncology), Hopital Beaujon, 92110 - Clichy/FR
  • 3Oncologie, Beaujon University Hospital, Clichy/FR
  • 4Oncology Department, CHU Cochin, 75014 - Paris/FR
  • 5Oncology Department, Beaujon University Hospital, Clichy/FR
  • 6Oncology, Cochin Hospital, 75014 - Paris/FR
  • 7Beaujon University Hospital, Clichy/FR



DTS-108 is a soluble pro-drug of SN38, the active metabolite of irinotecan, where the SN38 moiety is covalently linked to a 20AA peptide through a specific cross-linker that releases SN38 by esterase bond cleavage. DTS-108 was designed to achieve therapeutic levels of SN38, while reducing diarrhea.


SN-38 and SN-38G levels were evaluate with fluorescence HPLC test and LC/MS/MS methods. The pharmacokinetics of DTS-108, the adverse event (AE) profile, the dose limiting toxicities (DLT) at cycle 1, the maximum tolerated dose (MTD), and the recommended phase II dose (RD) of intravenous DTS-108 (1-2 hours) every two weeks (q2w) in patients (pts) with advanced/metastatic carcinomas was conducted.


Forty-Two pts received DTS-108 across 14 dosing cohorts (range: 3-416mg/m2). All grade AEs were asthenia (43%), nausea (43%), diarrhea (41%), vomiting (33%), anemia (31%), rash (21%), anorexia (21%), alopecia (19%), abdominal pain (19%), and neutropenia (19%). Neutropenia was the dose limiting toxicity of DTS-108. Neutropenia started to be observed at doses >56 mg/m2. At 416 mg/m2, 3/6 pts had grade 4 neutropenia. Fluorescence HPLC was initially used to quantify DTS-108 and its metabolites (SN-38 and SN-38G). Sample stability analysis of this method showed that SN38 values were inaccurate as DTS-108 degraded forming ex-vivo SN-38 during the blood collection, plasma storage, and/or sample extraction. New processes and analytical LC/MS/MS methods for testing SN-38 were implemented. At the dose of 313 mg/m2, mean DTS-108, SN38, and SN38G AUCINF (CV%) were 439293 (24%), 1992 (34%), and 4538 (46%) h*ng/mL. Tumor stabilization (RECIST) was observed in 9 pts and confirmed in 6 pts.


SN-38 concentration using Fluorescence HPLC failed to monitor drug escalation in topoisomerase I inhibitor because of ex vivo degradation. SN-38 exposures using LC/MS/MS methods are consistent with less variables values and allow drug monitoring. DTS-108 induced no dose-limiting diarrhea but neutropenia and infusion skin reactions. The dose level 313 mg/m2 was declared the MTD based on 5 of the 6 patients treated at this dose level having no dose-limiting neutropenia and the overall improvement in the management of infusion réactions.


All authors have declared no conflicts of interest.