A Phase I Dose Escalation and Bioavailability Study of Oral Sodium Phenylbutyrate in Patients with Refractory Solid Tumor Malignancies

A Phase I Dose Escalation and Bioavailability Study of Oral Sodium Phenylbutyrate in Patients with Refractory Solid Tumor Malignancies1

Divisions of Medical Oncology and Experimental Therapeutics, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-1000 [J. G., S. D. B., M. K. B., L. G., Y. Z., R. C. D., M. A. C.], and NIH, Bethesda, Maryland 20892 [W. D. F.]

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.

Footnotes

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↵1 Supported by Grants UO-1 CA 70095 (to M. A. C.) and RO1 CA-75525 (to M. A. C.), CaPCURE Competitive Research Award, Aegon Scholarship in Oncology (to J. G.), and Johns Hopkins General Clinical Research Center Grant MOIRR00052 (to M. A. C.).
↵2 To whom requests for reprints should be addressed, at Johns Hopkins Oncology Center, 1 M88 Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231-1000. Phone: (410) 614-3977; Fax: (410) 614-9006; E-mail: carducci{at}jhmi.edu
↵3 The abbreviations used are: PB, phenylbutyrate; PT, prothrombin time; PTT, partial thromboplastin time; ECOG, Eastern Cooperative Oncology Group; T_max, time to maximum plasma concentration; C_max, maximum plasma concentration; PG, phenylacetylglutamine; PA, phenylacetate; AUC, area under the curve; QOL, quality of life assessment; t_1/2, half-time; EORTC, European Organization for Research and Treatment of Cancer; CNS, central nervous system; MTD, maximum tolerated dose; PSA, prostate-specific antigen; HDAC, histone deacetylase inhibitor.
↵4 Carducci, M. A., Gilbert, J., Bowling, M. K., Noe, D., Eisenberger, M., Sinibaldi, V., Zabelina, Y., Chen, T., Grochow, L. B., and Donehower, R. C. Phenylbutyrate for refractory solid tumors: Phase I clinical and pharmacological evaluation of i.v. and oral phenylbutyrate, manuscript in preparation.
- Accepted May 1, 1901.
- Received January 31, 1901.
- Revision received April 13, 1901.