A Phase I Clinical and Pharmacological Evaluation of Sodium Phenylbutyrate on an 120-h Infusion Schedule 1 Michael A. Carducci, 2 Jill Gilbert, M. Katherine Bowling, Dennis Noe, Mario A. Eisenberger, Victoria Sinibaldi, Yelena Zabelina, Tian-ling Chen, Louise B. Grochow, and Ross C. Donehower 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, phar- macokinetics, and antitumor effects in patients with refrac- tory 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 per- formed 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 predom- inant 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 hy- peruricemia. 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 demon- strated that plasma clearance of PB increased in a continu- ous 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 accumu- lated progressively. Plasma PB concentrations (at 410 mg/ kg/day) remained above the targeted therapeutic threshold of 500 mol/liter required for in vitro activity. Conclusion: The DLT in this Phase I study for infu- sional 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. INTRODUCTION Differentiation therapy for epithelial malignancies may po- tentially alter tumor growth and progression, slow or inhibit metastases, inhibit angiogenesis, and/or effect response to other forms of therapy (1–5). Nonretinoid agents such as hexameth- ylenebisacetamide and sodium butyrate have been evaluated clinically, but sustained systemic levels required for activity have not been achieved because of toxicity and/or lack of a suitable formulation (6 –9). Sodium PB, 3 an aromatic fatty acid, is a lead candidate as a cancer differentiating agent and a histone deacetylase inhibitor (10 –13). Sodium PB is the precursor to PA, and both compounds are potent differentiating agents in vitro (10 –18). PA is formed by -oxidation of PB (19). PB is Food and Drug Administration approved for children and adults with hyperammonemia associated with urea cycle disorders (recommended dose of 13 g/m 2 /day) and has been used for adult patients with hyperammonemia secondary to high-dose chemo- therapy for leukemia and transplant therapies (19 –22). PB is also under investigation for cystic fibrosis and adrenal leukodys- trophy. Preclinical studies have looked at the ability of these drugs to alter gene expression and promote differentiation (23–25). In various tumor model systems, PA/PB can arrest cells in G 1 -G 0 with induction of p21 WAF1 and other cdk-2-associated cell cycle checkpoint proteins, alter expression of invasion products such as urokinase-plasminogen activator (UPA), induce apoptosis, inhibit telomerase, and increase MHC class I expression at concentrations of 500-2500 mol/liter PB (23–31). Delay in tumor progression has been noticed in prostate and malignant glioma models (12, 16, 17). It should be noted that tumor markers, such as PSA, might not be the most accurate measure- ments of progressive disease in patients treated with PB, as a rise in tumor markers may signal cell differentiation rather than Received 3/14/01; revised 6/11/01; accepted 6/13/01. 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 Oncol- ogy 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@jhmi.edu. 3 The abbreviations used are: PB, phenylbutyrate; PA, phenylacetate; PG, phenylacetylglutamine; PSA, prostate-specific antigen; MTD, max- imum tolerated dose; NCI, National Cancer Institute; DLT, dose-limit- ing toxicity; PCA, prostate cancer. 3047 Vol. 7, 3047–3055, October 2001 Clinical Cancer Research Research. on October 18, 2021. © 2001 American Association for Cancer clincancerres.aacrjournals.org Downloaded from