Phase I Trial of Valproic Acid and Epirubicin in Solid Tumor Malignancies
This is a Phase I dose escalation trial with escalating doses of Valproic acid and one dose
escalation step of epirubicin. VPA will be escalated starting at a dose that is recommended
for use as an anti-convulsant or to treat migraine headaches. Recommended concentrations for
seizure control is 15-60 mg/kg. Pharmacokinetic studies from healthy volunteers and patients
suggested a linear increase in plasma concentrations. A daily dosing of 16 mg/kg divalproex
(delayed-release VPA) resulted in a peak VPA plasma concentration of 127 μg/ml (~0.9 mM) 27.
The recommended Phase II dose of VPA was 60 mg/kg/d when given by a one-hour intravenous
infusion twice daily for 5 days every three weeks.
Synergistic activity between VPA and epirubicin has been observed at 0.5 mM of VPA in our
preclinical laboratory studies. Patients will receive an intravenous loading dose of VPA
followed by divalproex in two daily doses for 5 doses. The loading dose of VPA will avoid a
delay in peak plasma concentrations and excessive nausea. Epirubicin will be given by
infusion on day 3 after the last dose of divalproex.
Once the MTD for this two drug regimen has been determined, the maximum tolerated dose will
be determined as part of the FEC regimen (5-fluorouracil, epirubicin and cyclophosphamide).
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Pamela Munster, MD
H. Lee Moffitt Cancer Center and Research Institute
United States: Food and Drug Administration
|H. Lee Moffitt Cancer Center & Research Institute||Tampa, Florida 33612|