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

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/m(2)). At 416 mg/m(2), three out of six patients had grade 4 neutropenia thereby defining the MTD and the RP2D at 313 mg/m(2). 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/m(2), 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/m(2). The RP2D for intravenous DTS-108 was 313 mg/m(2) every 2 weeks in patients with advanced/metastatic solid tumors.