Pharmacodynamics (PD) and pharmacokinetics (PK) of E7389 (eribulin, halichondrin B analog) during a phase I trial in patients with advanced solid tumors: a California Cancer Consortium trial.

BACKGROUND: The California Cancer Consortium completed a phase I trial of E7389 (eribulin mesylate), an analog of the marine natural product halichondrin B. This trial was to determine the pharmacodynamics, pharmacokinetics, and MTD of E7389 administered by bolus injection weekly for 3 weeks out of four. METHODS: This trial included a rapid titration design. Real-time pharmacokinetics were utilized to guide dose escalation. Initially, single-patient cohorts were enrolled with intra- and inter-patient dose doubling. The second phase was a standard 3 + 3 dose escalation schedule. At the MTD, a cohort of patients was enrolled for target validation studies (separate manuscript). The starting dose was 0.125 mg/m(2), and doses were doubled within and between patients in the first phase. Blood and urine sampling for E7389 pharmacokinetics was performed on doses 1 and 3 of cycle 1. Levels were determined using a LC/MS/MS assay. RESULTS: Forty patients were entered. Thirty-eight were evaluable for toxicity and 35 for response. The rapid escalation ended with a grade 3 elevation of alkaline phosphatase at 0.5 mg/m(2)/week. The second phase ended at 2.0 mg/m(2)/week with dose-limiting toxicities of grades 3 and 4 febrile neutropenia. Other toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m(2)/week. Responses included four partial responses (lung cancer [2], urothelial [1], and melanoma [1]). CONCLUSIONS: E7389 was well tolerated in this trial with the major toxicity being myelosuppression. PD shows that E7389 induces significant morphologic changes (bundle formation) in the microtubules of peripheral blood mononuclear cells and tumor cells in vivo. The data suggest that lower intra-tumoral levels of ß-tubulin III or higher intra-tumoral levels of MAP4 may correlate with response to E7389, while lower intra-tumoral levels of stathmin may be associated with progression. PK data reveal that E7389 exhibits a tri-exponential elimination from the plasma of patients receiving a rapid i.v. infusion. At sub-toxic doses, plasma concentrations of E7389 are maintained well above the levels required for activity in vitro for >72 h.

Development of peptide-based lineage-specific serology for chronic Chagas disease: geographical and clinical distribution of epitope recognition.

BACKGROUND: Chagas disease, caused by infection with the protozoan Trypanosoma cruzi, remains a serious public health issue in Latin America. Genetically diverse, the species is sub-divided into six lineages, known as TcI-TcVI, which have disparate geographical and ecological distributions. TcII, TcV, and TcVI are associated with severe human disease in the Southern Cone countries, whereas TcI is associated with cardiomyopathy north of the Amazon. T. cruzi persists as a chronic infection, with cardiac and/or gastrointestinal symptoms developing years or decades after initial infection. Identifying an individual's history of T. cruzi lineage infection directly by genotyping of the parasite is complicated by the low parasitaemia and sequestration in the host tissues. METHODOLOGY/PRINCIPAL FINDINGS: We have applied here serology against lineage-specific epitopes of the T. cruzi surface antigen TSSA, as an indirect approach to allow identification of infecting lineage. Chagasic sera from chronic patients from a range of endemic countries were tested by ELISA against synthetic peptides representing lineage-specific TSSA epitopes bound to avidin-coated ELISA plates via a biotin labelled polyethylene glycol-glycine spacer to increase rotation and ensure each amino acid side chain could freely interact with their antibodies. 79/113 (70%) of samples from Brazil, Bolivia, and Argentina recognised the TSSA epitope common to lineages TcII/TcV/TcVI. Comparison with clinical information showed that a higher proportion of Brazilian TSSApep-II/V/VI responders had ECG abnormalities than non-responders (38% vs 17%; p<0.0001). Among northern chagasic sera 4/20 (20%) from Ecuador reacted with this peptide; 1/12 Venezuelan and 1/34 Colombian samples reacted with TSSApep-IV. In addition, a proposed TcI-specific epitope, described elsewhere, was demonstrated here to be highly conserved across lineages and therefore not applicable to lineage-specific serology. CONCLUSIONS/SIGNIFICANCE: These results demonstrate the considerable potential for synthetic peptide serology to investigate the infection history of individuals, geographical and clinical associations of T. cruzi lineages.