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Phase I/II trial of Arginine Butyrate and ganciclovir in Epstein-Barr virus-associated lymphoid malignancies



Phase I/II trial of Arginine Butyrate and ganciclovir in Epstein-Barr virus-associated lymphoid malignancies



Journal of Clinical Oncology 24(18_suppl): 7542-7542



NlmCategory="UNASSIGNED">7542 Background: Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type anti-viral 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(+) lymphoblastoid cells, tumor lines and primary lymphoma cultures 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 heavily-pretreated, refractory EBV(+) lymphoid malignancies, consisting of monoclonal refractory lymphoproliferative disease (PTLD), B cell non-Hodgkin's lymphomas (NHL) (including one HIV-associated anaplastic B cell lymphoma), T cell NHL (including one cutaneous lymphoma), T/NK cell lymphomas, and Hodgkin disease were studied. Ganciclovir was administered twice daily and Arginine Butyrate 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. The MTD for Arginine Butyrate was established as 1000 mg/kg/day. Overall the combination was well-tolerated, with the most common toxicities being nausea and headache. Complications from rapid tumor lysis occurred in three patients, including acute hepatic necrosis in one patient. Reversible grade 3-4 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, with 5 CR and 5 PR. In certain patients who demonstrated a clinical CR, subsequent pathological analysis showed elimination of all tumor cells. The combination of Arginine Butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biological activity in vitro and in vivo against refractory EBV(+) lymphoid malignancies. No significant financial relationships to disclose.

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Accession: 058542613

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PMID: 27955470



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