A Phase I/II Study of Arginine Butyrate and Ganciclovir in Patients with Epstein-Barr Virus-Associated Lymphoid Malignancies.

Malignancies associated with latent Epstein-Barr virus are resistant to nucleoside-type antiviral agents because the viral enzyme target of these drugs, thymidine kinase (TK), is not expressed. Short-chain fatty acids, such as butyrate, induce EBV-TK expression in latently-infected B cells. In preclinical studies, we have shown that butyrate sensitizes EBV(+) lymphoid cells and tumor lines to apoptosis induced by ganciclovir. We conducted a Phase I/II trial of Arginine Butyrate in combination with ganciclovir in patients with refractory EBV(+) lymphoid malignancies to evaluate toxicity, pharmacokinetic parameters, and clinical responses. Fifteen patients with refractory EBV(+) lymphoid malignancies, including monoclonal lymphoproliferative disease (PTLD), B cell non-Hodgkin’s lymphomas (NHL), T cell NHL (including one panniculytic subcutaneous lymphoma), T/NK cell lymphomas, and Hodgkin’s disease were studied. The patients had been relatively heavily pretreated with chemotherapy and/or radiation before entry into this study. In this study, ganciclovir was administered twice daily at approved doses and Arginine Butyrate (AB) was administered in an intra-patient dose-escalation. Arginine Butyrate was instituted at 500 mg/kg/day by continuous infusion, and escalated to 2000 mg/kg/day, as tolerated. Pharmacokinetic studies were performed. The MTD for Arginine Butyrate when administered in combination with ganciclovir was established as 1000 mg/kg/day by continuous infusion. Overall, the combination was well-tolerated, with the most common toxicities being nausea, headache. Complications from rapid tumor lysis occurred in three patients, including acute hepatic necrosis in one patient. Reversible somnolence or stupor occurred in three patients at Arginine Butyrate doses of greater than 1000 mg/kg/day. Ten of fifteen patients showed significant anti-tumor responses within 10 days of initiation of treatment, with 5 CR and 5 PR. In some of the patients who demonstrated a CR, subsequent pathological analysis showed no residual tumor cells. The combination of Arginine Butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biological activity in vivo against EBV(+) lymphoid malignancies. Further trials, especially in patients with earlier stage disease, appear warranted.