Bahleda R, et al. - Phase I trial of bortezomib daily dose was performed to assess if daily low dose administration of bortezomib could allow a greater and tolerable pharmacokinetic exposure which might be required for antitumor activity in solid tumors. In this study, the daily subcutaneous regimen of bortezomib demonstrated a dose-dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. However, increasing neurological toxicity of this dose-dense daily regimen might hinder its further clinical development.

Methods

• Researchers performed this 3 + 3 design, dose escalation, monocentric study to define the maximum tolerated dose of daily low dose schedule of bortezomib.
• In addition, they evaluated tolerability, pharmacokinetics, pharmacodynamics, antitumor activity, biomarkers for proteasome inhibition, pre- and post-treatment tumor biopsies.

Results

• They dosed a total of eighteen patients in 3 bortezomib cohorts (0.5, 0.6 and 0.7 mg/m²), with 3, 11 and 4 patients respectively.
• Dose-limiting toxicities were evident in 3 patients: Grade (G) 3 Sweet's syndrome (at 0.6 mg/m2), G3 asthenia and anorexia or ataxia (2 patients at 0.7 mg/m2).
• Drug-related adverse events most commonly noticed (all grades) were thrombocytopenia (72%), fatigue (56%), neuropathy (50%), anorexia (44%) and rash (39%).
• Researchers considered dose 0.6 mg/m² of bortezomib as the recommended phase II dose.
• They observed a significant tumor shrinkage (-36% according to WHO criteria) in one patient with heavily pre-treated GIST, and 2 minor responses (-20%) in two patients with melanoma and mesothelioma.