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.

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

Supplementary material

Table S1 Noncompartmental pharmacokinetic parameters for DTS-108, SN-38, and SN-38G

Acknowledgments

We gratefully acknowledge the nursing staff of Departments of Medical Oncology, Hôpital Beaujon and Hôpital Cochin, for their assistance. Drais Pharmaceuticals sponsored this clinical trial.

Data have been presented at the American Society for Clinical Oncology meeting 2012 in Chicago (abstract no 2557) and at the European Society for Clinical Oncology meeting 2012 in Vienna (European Union Drug Regulating Authorities Clinical Trials registration number: 2008-004452-74).

Disclosure

RD is the director at Drais Pharmaceuticals and owns stock options in Drais Pharmaceuticals. The other authors report no conflicts of interest in this work.