Phase I and pharmacokinetic study of novobiocin in combination with VP-16 in patients with refractory malignancies

Abstract

Purpose: The coumarin antibiotic novobiocin potentiates the activity of etoposide (VP-16) in vitro by increasing intracellular accumulation of VP-16. The drug efflux pump inhibited by novobiocin appears to be distinct from both of the major proteins associated with the multidrug resistance phenotype in human cancers, the 170-kDa P-glycoprotein and the 190-kDa multidrug resistance protein. In a recent study, we found that novobiocin augmented VP-16 accumulation ex vivo in 16 of 24 fresh tumor samples at concentrations that could be achieved in vivo. Therefore, we conducted a clinical trial to determine the maximum tolerated dose and the pharmacokinetics of novobiocin when given in combination with VP-16.

Patients and methods: Patients with refractory cancer were treated with VP-16 on days 1, 3, and 5. Antiemetics, consisting of ondansetron and dexamethasone, were given 60 minutes before the VP-16 was administered. Novobiocin was given orally 30 minutes before the VP-16, and the dose was escalated in successive groups of patients according to a standard dose escalation design. Treatment cycles were repeated every 4 weeks. Plasma concentrations of novobiocin were determined during the first treatment cycle by high-performance liquid chromatography.

Results: Thirty-three patients were treated for a total of 69 cycles. Eleven patients were treated with a starting dose of VP-16 of 120 mg/m2, and three of these patients experienced neutropenic fever. The dose of VP-16 was reduced to 100 mg/m2, and an additional 22 patients were enrolled. The dose of novobiocin ranged from 3 to 9 g. At a novobiocin dose of at least 5.5 g, plasma concentrations of at least 150 microM were sustained for 24 hours. Dose-limiting toxicities consisted of neutropenic fever and reversible hyperbilirubinemia. Nausea, which was a limiting toxicity in other trials of novobiocin, was well controlled with the use of serotonergic antiemetics. Diarrhea was common but mild in most patients.

Discussion: In previously treated patients, the recommended dose of novobiocin in this schedule is 7 g/m2/day. Novobiocin does not appear to augment the toxicity of VP-16 to the bone marrow or the gastrointestinal mucosa. Plasma concentrations of novobiocin equivalent to the levels required to modulate VP-16 in vitro are readily achievable for total but not unbound free drug.