Verubulin (MPC-6827) is a microtubule-destabilizing agent that achieves high concentrations in the brain.
Verubulin disrupts newly formed blood vessels in xenografts. We determined the safety and tolerability of
verubulin administered in combination with
carboplatin in patients with relapsed
glioblastoma multiforme (GBM). Three pre-selected doses of
verubulin were tested: 2.1, 2.7, and 3.3 mg/m(2) in a standard "3+3" design.
Verubulin was given every second week of a 6-week cycle in the 2.1 mg/m(2) cohort or weekly for 3 weeks of a 4-week cycle in subsequent cohorts.
Carboplatin was administered intravenously at an area under the curve (AUC) dosage 4 every 2 weeks for the 2.1 mg/m(2) cohort or on day 1 of each 4-week cycle in subsequent cohorts. Nineteen patients with GBM in first or second relapse were enrolled. Four patients (21 %) experienced a grade 3 or greater
verubulin- or
carboplatin-related adverse event, including
hypesthesia,
cerebral ischemia,
anemia, and
thrombocytopenia. The mean plasma half life of
verubulin was 3.2 h (SD = 0.82). Two patients achieved at least a partial response by Macdonald criteria. One of these patients remains progression free and off treatment more than 24 months beyond his initiation of
verubulin. Five patients had stable disease. Median progression-free survival (PFS) across all patients was 8 weeks, and the 6-month PFS rate was 21 %. The combination of
verubulin at the previously determined single-agent maximum tolerated dose of 3.3 mg/m(2) with
carboplatin in patients with recurrent/refractory GBM is safe and well tolerated. In this patient population with a highly vascularized
tumor, no
cerebral hemorrhage was observed.