er-086526 and Melanoma

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.. 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.. 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]).. 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 β-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.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Dose-Response Relationship, Drug; Drug Monitoring; Febrile Neutropenia; Female; Furans; Humans; Injections, Intravenous; Ketones; Lung Neoplasms; Lymphopenia; Male; Melanoma; Middle Aged; Ovarian Neoplasms; Salvage Therapy; Tubulin Modulators; Urologic Neoplasms

Eribulin is used in many countries to treat patients with advanced breast cancer or liposarcoma and exerts in vivo anticancer activity under monotherapy conditions against various human tumor xenograft models. Here, eribulin in combination with mechanistically different anticancer agents was evaluated.. Eribulin was combined with cytotoxic agents (capecitabine, carboplatin, cisplatin, doxorubicin, gemcitabine) or targeted agents (bevacizumab, BKM-120, E7449, erlotinib, everolimus, lenvatinib, palbociclib) in tumor xenograft models of breast cancer, melanoma, non-small cell lung cancer (NSCLC), and ovarian cancer.. Across nearly all models, eribulin with either cytotoxic or targeted agents demonstrated combination activity, defined as the activity demonstrably greater than that of either agent alone. Combination activity was absent only with doxorubicin (MDA-MB-435 model) and with lenvatinib (NCI-H1975 model), both of which responded to the agents as monotherapy.. Eribulin has combination activity with multiple agents from different mechanistic classes in several human cancer models, including breast, NSCLC, ovarian, and melanoma.

Topics: A549 Cells; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Synergism; Female; Furans; Humans; Ketones; Lung Neoplasms; MCF-7 Cells; Melanoma; Mice; Neoplasms; Ovarian Neoplasms; Xenograft Model Antitumor Assays

Eribulin, a synthetic analog of the natural product halichondrin B, is a microtubule dynamics inhibitor. In this study, we report the pharmacokinetic profiles of eribulin in mice, rats, and dogs following intravenous administrations with optimized and validated bio-analytical methods.. Eribulin was administered at 0.5 and 2 mg/kg in mice, 0.5 and 1 mg/kg in rats, and 0.08 mg/kg in dogs. Tumor and brain penetration of eribulin was also evaluated in LOX human melanoma xenograft models. Concentrations in plasma, tumor, and brain were measured by the LC-MS/MS method.. The profiles of eribulin were characterized by extensive distribution, moderate clearance, and slow elimination in the three species. The pharmacokinetics are linear in mice and rats. In xenograft mice, the penetration into the brain was low, as expected, since eribulin is a P-glycoprotein substrate. In contrast to disposition in brain, the exposure of eribulin was approximately 20-30 times higher in tumor than that in plasma and half-lives were 17.8-35.9 h after both single and multiple dose regimens.. Eribulin was distributed rapidly and eliminated slowly in mice, rats, and dogs. The exposure of eribulin was approximately 20-30 times higher in tumor than in plasma in xenograft mice. These results might be caused by eribulin's mechanism of action including increased perfusion in tumor by vascular remodeling effect.

Topics: Animals; Antineoplastic Agents; Brain; Chromatography, Liquid; Dogs; Dose-Response Relationship, Drug; Female; Furans; Half-Life; Humans; Ketones; Male; Melanoma; Mice; Mice, Inbred BALB C; Rats; Rats, Sprague-Dawley; Species Specificity; Tandem Mass Spectrometry; Tissue Distribution; Vascular Remodeling; Xenograft Model Antitumor Assays