Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors

Autor: Michael J. Hanley, Eric Deutsch, Audrey Poterie, Christophe Massard, Andreea Varga, Mehdi Touat, Rastislav Bahleda, Damien Ricard, Anas Gazzah, Shalini Chaturvedi, Helgi van de Velde, Jean-Charles Soria, Vincent Ribrag, M. Sallansonnet-Froment, Marie-Cécile Le Deley, Apexa Bernard, Eric Angevin, Hervé Taillia, Antoine Hollebecque
Rok vydání: 2017
Předmět:
Zdroj: Investigational New Drugs. 36:619-628
ISSN: 1573-0646
0167-6997
DOI: 10.1007/s10637-017-0531-3
Popis: Purpose This phase I study investigated bortezomib in solid tumors used as a daily subcutaneous regimen. Previous regimens showed only modest activity in solid tumors which was potentially related to sub-optimal tumor penetration. We aimed at exploring if daily low dose administration of bortezomib may allow a greater and tolerable pharmacokinetic exposure which might be required for antitumor activity in solid tumors. Patients and methods This 3 + 3 design, dose escalation, monocentric study aimed at defining the maximum tolerated dose of daily low dose schedule of bortezomib. Tolerability, pharmacokinetics, pharmacodynamics, antitumor activity, biomarkers for proteasome inhibition, pre- and post-treatment tumor biopsies were also evaluated. Results A total of eighteen patients were dosed in 3 bortezomib cohorts (0.5, 0.6 and 0.7 mg/m2), with 3, 11 and 4 patients respectively. Three patients experienced dose-limiting toxicities: Grade (G) 3 Sweet's syndrome (at 0.6 mg/m2), G3 asthenia and anorexia or ataxia (2 patients at 0.7 mg/m2). The most common study drug-related adverse events (all grades) were thrombocytopenia (72%), fatigue (56%), neuropathy (50%), anorexia (44%) and rash (39%). Dose 0.6 mg/m2 of bortezomib was considered as the recommended phase II dose. A significant tumor shrinkage (-36% according to WHO criteria) was observed in one patient with heavily pre-treated GIST, and 2 minor responses (-20%) were recorded in two patients with melanoma and mesothelioma. Conclusion This daily subcutaneous regimen of bortezomib showed a dose dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. However, cumulative neurological toxicity of this dose-dense daily regimen might preclude its further clinical development.
Databáze: OpenAIRE
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