A Phase I Clinical and Pharmacological Evaluation of Sodium Phenylbutyrate on an 120-h Infusion Schedule

A Phase I Clinical and Pharmacological Evaluation of Sodium Phenylbutyrate on an 120-h Infusion Schedule1

Divisions of Medical Oncology [M. A. C., J. G., M. K. B., M. A. E., V. S., L. B. G., R. C. D.] and Experimental Therapeutics and Pharmacology [M. A. C., D. N., Y. Z., T-l. C., L. B. G.], The Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231

Abstract

Purpose: Sodium phenylbutyrate (PB) demonstrates potent differentiating capacity in multiple hematopoietic and solid tumor cell lines. We conducted a Phase I and pharmacokinetic study of PB by continuous infusion to characterize the maximum tolerated dose, toxicities, pharmacokinetics, and antitumor effects in patients with refractory solid tumors.

Patients and Methods: Patients were treated with a 120-h PB infusion every 21 days. The dose was escalated from 150 to 515 mg/kg/day. Pharmacokinetics were performed during and after the first infusion period using a validated high-performance liquid chromatographic assay and single compartmental pharmacokinetic model for PB and its principal metabolite, phenylacetate.

Results: A total of 24 patients were enrolled on study, with hormone refractory prostate cancer being the predominant tumor type. All patients were evaluable for toxicity and response. A total of 89 cycles were administered. The dose-limiting toxicity (DLT) was neuro-cortical, exemplified by excessive somnolence and confusion and accompanied by clinically significant hypokalemia, hyponatremia, and hyperuricemia. One patient at 515 mg/kg/day and another at 345 mg/kg/day experienced this DLT. Toxicity resolved ≤12 h of discontinuing the infusion. Other toxicities were mild, including fatigue and nausea. The maximum tolerated dose was 410 mg/kg/day for 5 days. Pharmacokinetics demonstrated that plasma clearance of PB increased in a continuous fashion beginning 24 h into the infusion. In individuals whose V_max for drug elimination was less than their drug-dosing rate, the active metabolite phenylacetate accumulated progressively. Plasma PB concentrations (at 410 mg/kg/day) remained above the targeted therapeutic threshold of 500 μmol/liter required for in vitro activity.

Conclusion: The DLT in this Phase I study for infusional PB given for 5 days every 21 days is neuro-cortical in nature. The recommended Phase II dose is 410 mg/kg/day for 120 h.

Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 Supported by UO-1 CA 70095, American Society of Clinical Oncology Young Investigator Award; NIH-K08-CA-69164; NIH-R01-CA75525 (to M. A. C.); Aegon Scholarship in Oncology (to J. G.), General Clinical Research Center N01-CM07302 from the National Cancer Institute.
↵2 To whom requests for reprints should be addressed, at The Johns Hopkins Oncology Center, 1 M88 Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231-1000. E-mail: carducci{at}jhmi.edu
↵3 The abbreviations used are: PB, phenylbutyrate; PA, phenylacetate; PG, phenylacetylglutamine; PSA, prostate-specific antigen; MTD, maximum tolerated dose; NCI, National Cancer Institute; DLT, dose-limiting toxicity; PCA, prostate cancer.
↵4 S. Gore, personal communication.
↵5 M. A. Carducci, R. Pili, unpublished data.
- Accepted June 13, 1901.
- Received March 14, 1901.
- Revision received June 11, 1901.