A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies.

Abstract

PURPOSE:

Phenylbutyrate (PB) is an aromatic fatty acid with multiple mechanisms of action including histone deacetylase inhibition. Preclinically, PB demonstrates both cytotoxic and differentiating effects at a concentration of 0.5 mM. We conducted a Phase I trial of p.o. PB patients with refractory solid tumor malignancies to evaluate toxicity, pharmacokinetic parameters, and feasibility of p.o. administration.

EXPERIMENTAL DESIGN:

Twenty-eight patients with refractory solid tumor malignancies were enrolled on this dose-escalation to maximally tolerated dose trial. Five dose levels of PB were studied: 9 g/day (n = 4), 18 g/day (n = 4), 27 g/day (n = 4), 36 g/day (n = 12), and 45 g/day (n = 4). Pharmacokinetic studies were performed and included an p.o. bioavailability determination. Compliance data were also collected.

RESULTS:

The recommended Phase II dose is 27 g/day. Overall the drug was well tolerated with the most common toxicities being grade 1-2 dyspepsia and fatigue. Nonoverlapping dose-limiting toxicities of nausea/vomiting and hypocalcemia were seen at 36 g/day. The p.o. bioavailability of PB was 78% for all dose levels, and the biologically active concentration of 0.5 mM was achieved at all dose levels. Compliance was excellent with 93.5% of all possible doses taken. No partial remission or complete remission was seen, but 7 patients had stable disease for more than 6 months while on the drug.

CONCLUSIONS:

PB (p.o.) is well tolerated and achieves the concentration in vivo that has been shown to have biological activity in vitro. PB may have a role as a cytostatic agent and should be additionally explored in combination with cytotoxics and other novel drugs.

• Authors: J Gilbert, S D Baker, M K Bowling, L Grochow, W D Figg, Y Zabelina, R C Donehower, M A Carducci
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 7 Issue 8 Pg. 2292-300 (Aug 2001) ISSN: 1078-0432 [Print] United States
• PMID: 11489804 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Phenylacetates
• Phenylbutyrates
• Glutamine
• phenylacetylglutamine
• phenylacetic acid

Topics

• Administration, Oral
• Adult
• Aged
• Area Under Curve
• Biological Availability
• Dose-Response Relationship, Drug
• Edema (chemically induced)
• Fatigue (chemically induced)
• Female
• Glutamine (analogs & derivatives, blood)
• Humans
• Hypocalcemia (chemically induced)
• Male
• Middle Aged
• Nausea (chemically induced)
• Neoplasms (drug therapy, metabolism)
• Nervous System Diseases (chemically induced)
• Phenylacetates (blood)
• Phenylbutyrates (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome
• Vomiting (chemically induced)