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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.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2015 Nov; Vol. 76 (5), pp. 897-907. Date of Electronic Publication: 2015 Sep 11. - Publication Year :
- 2015
-
Abstract
- 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.<br />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.<br />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]).<br />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 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.
- Subjects :
- Adult
Aged
Aged, 80 and over
Antineoplastic Agents adverse effects
Antineoplastic Agents blood
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents therapeutic use
Breast Neoplasms blood
Breast Neoplasms drug therapy
Carcinoma blood
Dose-Response Relationship, Drug
Drug Monitoring
Febrile Neutropenia chemically induced
Female
Furans adverse effects
Furans blood
Furans pharmacokinetics
Furans therapeutic use
Humans
Injections, Intravenous
Ketones adverse effects
Ketones blood
Ketones pharmacokinetics
Ketones therapeutic use
Lung Neoplasms blood
Lung Neoplasms drug therapy
Lymphopenia chemically induced
Male
Melanoma blood
Melanoma drug therapy
Middle Aged
Ovarian Neoplasms blood
Ovarian Neoplasms drug therapy
Salvage Therapy
Tubulin Modulators adverse effects
Tubulin Modulators blood
Tubulin Modulators pharmacokinetics
Tubulin Modulators therapeutic use
Urologic Neoplasms blood
Urologic Neoplasms drug therapy
Antineoplastic Agents pharmacology
Carcinoma drug therapy
Furans pharmacology
Ketones pharmacology
Tubulin Modulators pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0843
- Volume :
- 76
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 26362045
- Full Text :
- https://doi.org/10.1007/s00280-015-2868-7