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/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.

Benefits from pharmacological and pharmacokinetic properties of sunitinib for clinical development.

IMPORTANCE OF THE FIELD: In the last 10 years, oncology has been greatly modified by the introduction of new drugs especially designed for molecular targets. Sunitinib belongs to the category of new drugs that inhibit multityrosine kinase receptors involved in the key steps of tumorigenesis and angiogenesis. AREAS COVERED IN THIS REVIEW: This article reviews the pharmacological and clinical aspects of sunitinib. Literature search was conducted in PubMed, and articles selected for relevance to pharmacology or clinical efficacy up to March 2010. WHAT THE READER WILL GAIN: Pharmacology of sunitinib, data regarding clinical efficacy, and challenges to overcome resistance and improve outcomes of patients. TAKE HOME MESSAGE: Sunitinib is an oral small molecule that displays mainly antiangiogenic properties and also direct antitumoral effects. Being well tolerated, this small molecule is now an essential treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors refractory or intolerant to imatinib, two localizations associated with a poor prognosis. Future developments include the extension of the indications of sunitinib in pancreatic neuroendocrine tumors, the evaluation of combinations with conventional cytotoxic and other targeted drugs and the development of strategy to overcome resistance to sunitinib.