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

Clin Cancer Res. 2001 Aug;7(8):2292-300.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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


  • Phenylacetates
  • Phenylbutyrates
  • Glutamine
  • phenylacetylglutamine
  • phenylacetic acid