Study of Cytolytic Viral Activation Therapy (CVAT) for Recurrent/Metastatic Nasopharyngeal Carcinoma

Summary

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus(EBV) related malignancy and is an endemic disease in Southeast Asian countries. EBV had been identified as a therapeutic target in some EBV related cancer such as lymphoma and NPC. In cancer cell, EBV was in latent phase and expressed 8-11 genes for maintaining EBV proliferation. After switching to lytic phase, almost all the EBV encoding genes were expressed including thymidine kinase (TK) and some highly immunogenetic genes. These latent-lytic phase swifter included DNA methyltransferase inhibitors, various histone deacetylase (HDAC) inhibitors, radiotherapy and chemotherapy. Recently, combined chemotherapy and viral lytic therapy, cytolytic viral activation therapy (CVAT) had been shown some promising result in pilot study of NPC. In our patient derived xenograft (PDX) animal model drug sensitivity screening, gemcitabine (GEM) was shown to be the most effective drug. Furthermore, CVAT with GEM + Valproic acid (VPA) + ganciclovir (GCV) maintaining chemotherapy may benefit but reduce chemotherapy related side effect and prolonging treatment response duration. The following phase I clinical trial will be proposed to test the optimal combination of these drugs. 1. Number of patients: total 18 patients are needed 2. Inclusion criteria:(1) used as 2nd line regimen in recurrence/metastasis NPC patients with tissue proved of World Health Organization (WHO) type II or type III.(2) Performance status: eastern cooperative oncology group performance status (ECOG PS) ≤2. 3. Chemotherapy regimen: Gemcitabine (GEM, TTY) + Valproic acid (VPA, generic medicine) for viral activation + Valganciclovir (VGC, Roche) for antiviral medication 4. This treatment cycle of 28 days was repeated maximum 6 times. (Q4wks/cycle, max: 6 cycles) 5. Dosage: (1) GEM: 600, 800, 1000, 1250 mg/m\^2, D1 \& D8, intravenously. (2) VPA 12.5 mg/kg/day D1\~14, per os. (3) VGC (2-3) x 450 mg/day D9\~15, per os. 6. Objectives: 1. primary: to find the best combination of these 3 drugs in recurrent/metastatic NPC patients. 2. second: to evaluate the response and disease control rate in this pilot study. Key words: NPC, cytolytic viral activation therapy, gemcitabine, valproic acid, ganciclovir.

Timeline

Start

2016-05

Primary completion

2017-06

Completion

—

Publications

• Background Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Ann Oncol. 2006 May;17 Suppl 5:v7-12. doi: 10.1093/annonc/mdj941.
• Background Wang LR, Liu J, Huang MZ, Xu N. Comparison of pharmacokinetics, efficacy and toxicity profile of gemcitabine using two different administration regimens in Chinese patients with non-small-cell lung cancer. J Zhejiang Univ Sci B. 2007 May;8(5):307-13. doi: 10.1631/jzus.2007.B0307.
• Background Noble S, Goa KL. Gemcitabine. A review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs. 1997 Sep;54(3):447-72. doi: 10.2165/00003495-199754030-00009.
• Background Natale R. A ten-year review of progress in the treatment of non-small-cell lung cancer with gemcitabine. Lung Cancer. 2005 Oct;50 Suppl 1:S2-4. doi: 10.1016/s0169-5002(05)81549-1.
• Background Bensouda Y, Kaikani W, Ahbeddou N, Rahhali R, Jabri M, Mrabti H, Boussen H, Errihani H. Treatment for metastatic nasopharyngeal carcinoma. Eur Ann Otorhinolaryngol Head Neck Dis. 2011 Apr;128(2):79-85. doi: 10.1016/j.anorl.2010.10.003. Epub 2010 Dec 21.
• Background Xu T, Tang J, Gu M, Liu L, Wei W, Yang H. Recurrent nasopharyngeal carcinoma: a clinical dilemma and challenge. Curr Oncol. 2013 Oct;20(5):e406-19. doi: 10.3747/co.20.1456.
• Background Chateauvieux S, Morceau F, Dicato M, Diederich M. Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. 2010;2010:479364. doi: 10.1155/2010/479364. Epub 2010 Jul 29.
• Background Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT, Craddock C, Turner BM. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia. 2005 Oct;19(10):1751-9. doi: 10.1038/sj.leu.2403910.
• Background Marchion DC, Bicaku E, Daud AI, Sullivan DM, Munster PN. Valproic acid alters chromatin structure by regulation of chromatin modulation proteins. Cancer Res. 2005 May 1;65(9):3815-22. doi: 10.1158/0008-5472.CAN-04-2478.
• Background Kuendgen A, Strupp C, Aivado M, Bernhardt A, Hildebrandt B, Haas R, Germing U, Gattermann N. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood. 2004 Sep 1;104(5):1266-9. doi: 10.1182/blood-2003-12-4333. Epub 2004 May 20.
• Background Ma BB, Chan AT. Recent perspectives in the role of chemotherapy in the management of advanced nasopharyngeal carcinoma. Cancer. 2005 Jan 1;103(1):22-31. doi: 10.1002/cncr.20768.
• Background Duenas-Gonzalez A, Candelaria M, Perez-Plascencia C, Perez-Cardenas E, de la Cruz-Hernandez E, Herrera LA. Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors. Cancer Treat Rev. 2008 May;34(3):206-22. doi: 10.1016/j.ctrv.2007.11.003. Epub 2008 Jan 15.
• Background Wildeman MA, Novalic Z, Verkuijlen SA, Juwana H, Huitema AD, Tan IB, Middeldorp JM, de Boer JP, Greijer AE. Cytolytic virus activation therapy for Epstein-Barr virus-driven tumors. Clin Cancer Res. 2012 Sep 15;18(18):5061-70. doi: 10.1158/1078-0432.CCR-12-0574. Epub 2012 Jul 3.
• Background Vaziri S, Pezhman Z, Sayyad B, Mansouri F, Janbakhsh A, Afsharian M, Najafi F. Efficacy of valganciclovir and ganciclovir for cytomegalovirus disease in solid organ transplants: A meta-analysis. J Res Med Sci. 2014 Dec;19(12):1185-92.
• Background Noble S, Faulds D. Ganciclovir. An update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients. Drugs. 1998 Jul;56(1):115-46. doi: 10.2165/00003495-199856010-00012.
• Background Len O, Gavalda J, Aguado JM, Borrell N, Cervera C, Cisneros JM, Cuervas-Mons V, Gurgui M, Martin-Davila P, Montejo M, Munoz P, Bou G, Carratala J, Torre-Cisneros J, Pahissa A; RESITRA. Valganciclovir as treatment for cytomegalovirus disease in solid organ transplant recipients. Clin Infect Dis. 2008 Jan 1;46(1):20-7. doi: 10.1086/523590.
• Background Ghosh SK, Perrine SP, Williams RM, Faller DV. Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents. Blood. 2012 Jan 26;119(4):1008-17. doi: 10.1182/blood-2011-06-362434. Epub 2011 Dec 7.
• Background Olson D, Gulley ML, Tang W, Wokocha C, Mechanic O, Hosseinipour M, Gold SH, Nguluwe N, Mwansambo C, Shores C. Phase I clinical trial of valacyclovir and standard of care cyclophosphamide in children with endemic Burkitt lymphoma in Malawi. Clin Lymphoma Myeloma Leuk. 2013 Apr;13(2):112-8. doi: 10.1016/j.clml.2012.11.003. Epub 2012 Dec 20.
• Background Stoker SD, Novalic Z, Wildeman MA, Huitema AD, Verkuijlen SA, Juwana H, Greijer AE, Tan IB, Middeldorp JM, de Boer JP. Epstein-Barr virus-targeted therapy in nasopharyngeal carcinoma. J Cancer Res Clin Oncol. 2015 Oct;141(10):1845-57. doi: 10.1007/s00432-015-1969-3. Epub 2015 Apr 29.
• Background Gnann Jr. JW. Antiviral therapy of varicella-zoster virus infections. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, Yamanishi K, editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. Chapter 65. Available from http://www.ncbi.nlm.nih.gov/books/NBK47401/
• Background Mascarenhas L, Malogolowkin M, Armenian SH, Sposto R, Venkatramani R. A phase I study of oxaliplatin and doxorubicin in pediatric patients with relapsed or refractory extracranial non-hematopoietic solid tumors. Pediatr Blood Cancer. 2013 Jul;60(7):1103-7. doi: 10.1002/pbc.24471. Epub 2013 Jan 17.
• Results Hsu CL, Kuo YC, Huang Y, Huang YC, Lui KW, Chang KP, Lin TL, Fan HC, Lin AC, Hsieh CH, Lee LY, Wang HM, Li HP, Chang YS. Application of a patient-derived xenograft model in cytolytic viral activation therapy for nasopharyngeal carcinoma. Oncotarget. 2015 Oct 13;6(31):31323-34. doi: 10.18632/oncotarget.5544.

Drugs

Indications