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

NCT02761291 | Unknown Phase 1 DMC

• 1 other identifier: 104-4750A
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief 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. 1.Number of patients: total 18 patients are needed
2. 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. 3.Chemotherapy regimen: Gemcitabine (GEM, TTY) + Valproic acid (VPA, generic medicine) for viral activation + Valganciclovir (VGC, Roche) for antiviral medication
4. 4.This treatment cycle of 28 days was repeated maximum 6 times. (Q4wks/cycle, max: 6 cycles)
5. 5.Dosage:
6. 6.primary: to find the best combination of these 3 drugs in recurrent/metastatic NPC patients.
7. 7.second: to evaluate the response and disease control rate in this pilot study.

Conditions

Nasopharyngeal Carcinoma

Keywords

Nasopharyngeal carcinoma; EB virus; metastasis; recurrence; cytolytic viral activation therapy; gemcitabine; valproic acid; ganciclovir; valganciclovir

Outcome Measures

Primary Outcomes (1)

• Number of participants suffered dose limiting toxicity (DLT) that are related to this treatment

  According to Worst Toxicity CTCAE v4.03 Grade and FDA indication of gemcitabine, the dose limiting toxicity (DLT) of this trial was determined in the first treatment cycle and DLTs were defined as ≥1 of the following effects attributable to the study drug and requiring discontinuation or a significant dose reduction in the study drug(s): 1. ≥Grade 4 neutropenia \>5 days; 2. ≥Grade 4 thrombopenia lasting ≥7 days; 3. ≥Grade 3 anemia; 4. ≥Grade 3 neutropenic fever with a single temperature of \>38.3 degree C or a sustained temperature of ≥ 38 degree C for more than one hour; 5. any ≥Grade 3 non-hematologic toxicity with exception of nausea and vomiting, alopecia, drug-related fever; 6. ≥Grade 3 serum creatinine; 7. bone marrow and renal function didn't recover to CTCAE Grade ≤ 1 of baseline at the Day 1 of the 2nd treatment course, the treatment can be postponed less than 2 weeks. DLT was recognized when the delayed duration was more than 2 weeks.

  The first treatment cycle (1~28 days approximately)

Secondary Outcomes (3)

• Safety and tolerability assessed by adverse events, serious adverse events

  3~6 months

• Overall Response Rate (ORR), according to RECIST criteria, assessed by CT/MRI for head and neck area/chest x-ray/abdominal echo/Gallium whole body tumor scan

  3~6 months in treatment, and 3~6 months in followed-up

• EB virus DNA load in plasma

  3~6 months in treatment, and 3~6 months in followed-up

Study Arms (1)

gemcitabine dose escalation

EXPERIMENTAL

In three combined drugs used in nasopharyngeal carcinoma, the valproic acid and valganciclovir administration will be followed by indication to find the maximum tolerance dose of gemcitabine.

Drug: Gemcitabine; Drug: Valproic acid; Drug: Valganciclovir

Interventions

Gemcitabine DRUG

Gemcitabine will be administrated 600\~1250 mg/m\^2 intravenously according to the body surface area at day 1 and day 8 in a 28 day-treatment cycle. The treatment cycle of 28 days will be repeated maximum 6 times. The first dose level of gemcitabine will be started at 800 mg/m\^2. If no subject suffered the dose limit toxicity, 1000 mg/m\^2 and even 1250 mg/m\^2 will be started by order. If subjects suffered the dose limit toxicity in 800 mg/m\^2, the 600 mg/m\^2 will be started.

Also known as: Gemmis

gemcitabine dose escalation

Valproic acid DRUG

Valproic acid will be administrated orally by the fixed dose 12.5 mg/kg/day according to instructions from day 1 to day 14 in one treatment cycle. The treatment cycle of 28 days will be repeated maximum 6 times.

Also known as: Depakine

gemcitabine dose escalation

Valganciclovir DRUG

Valganciclovir will be administrated orally by the fixed dose 1350 mg/day (creatinine clearance rate ≥ 60 mL/min) or 900 mg/day (creatinine clearance rate ≥ 40 mL/min and \< 60 mL/min) from day 9 to day 15 in one treatment cycle. The treatment cycle of 28 days will be repeated maximum 6 times.

Also known as: Valcyte

gemcitabine dose escalation

Eligibility Criteria

• Age: 20 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have the ability to understand and willingness to sign a written informed consent document
• Identified as recurrent nasopharyngeal carcinoma or distant metastases of male or female subjects who had failed in 1st line therapy including radiotherapy, not suitable for radiotherapy or unwilling to receive radiotherapy, 1st line chemotherapy excluding gemcitabine, and no curative treatment options
• Biopsy confirmed belong to World Health Organization classification of nasopharyngeal carcinoma type II or type III
• Men and women between aged 20 to 80 years of age; female patients with childbearing potential will routinely consult obstetric doctor for contraception and need to have contraception at least 6 months after finished this trial
• Adequate internal organs including liver, kidney and bone marrow function
• white blood cell count of \>3,000/µL; platelet count of ≥100,000/µL; absolute neutrophil count \>1,500/µL
• total bilirubin \<2.0 mg/dL, aspartate aminotransferase (AST), alanine transaminase(ALT) \<2.5x upper limit of normal range (ULN)
• serum creatinine \<2.0 mg/dL
• The daily performance status ECOG ≤ 2 points

You may not qualify if:

• Pregnancy or breast-feeding women, and plans within six months of pregnancy
• Contraindication to Gemmis injection, Depakine gastro-resistant tablet, and Valcyte film-coated tablets, including:
• Allergy to Gemmis injection, Depakine gastro-resistant tablet, Valcyte film-coated tablets, and other similar drugs
• Patients with hepatic B or C, patients with human immunodeficiency virus, or viral related disease receiving anti-viral treatment
• Acute or chronic hepatitis not related to NPC with liver metastasis
• Using drugs which ineligible combination with valproic acid, including mefloquine, St.-John's-Wort, lamotrigine, Topiramate, quetiapine, cyclosporin, hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine phenobarbital, primidone, rifampin), enzyme inhibitors (e.g., felbamate), aspirin, cimetidine, erythromycin, carbapenem (e.g., Panipenem, Aztreonam, Imipenem, Meropenem), diazepam, ethosuximide, lamotrigine, phenytoin, nimodipine
• With insomnia, anxiety or spiritual concerns, or are receiving mental illness treatment
• Has been diagnosed with a second cancer, except to basal cell carcinoma
• Patients unsuitable to this trial, including:
• Patients with significant disease
• PI evaluated with high risk group patients
• Patients not recovered from previous anti-cancer treatment
• Recent major surgery
• Patients with creatinine clearance rate \<40 ml/min

Sponsors & Collaborators

• Chang Gung Memorial Hospital: lead
• TTY Biopharm: collaborator

Study Sites (1)

Chang-Gung Memorial Hospital, Linkou

Taoyuan District, 333, Taiwan

RECRUITING

Related Publications (22)

• 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.

  PMID: 16807468 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.

  PMID: 17542057 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.

  PMID: 9279506 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.

  PMID: 16291427 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.

  PMID: 21177151 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.

  PMID: 24155638 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.

  PMID: 20798865 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.

  PMID: 16121216 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.

  PMID: 15867379 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.

  PMID: 15155466 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.

  PMID: 15565580 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.

  PMID: 18226465 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.

  PMID: 22761471 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.

  PMID: 25709661 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.

  PMID: 9664203 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.

  PMID: 18171208 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.

  PMID: 22160379 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.

  PMID: 23260601 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.

  PMID: 25920375 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/

  PMID: 21348091 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.

  PMID: 23335436 BACKGROUND

• 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.

  PMID: 26416517 RESULT

MeSH Terms

Conditions

Nasopharyngeal Carcinoma; Epstein-Barr Virus Infections; Neoplasm Metastasis; Recurrence; Multiple Acyl Coenzyme A Dehydrogenase Deficiency

Interventions

Gemcitabine; Valproic Acid; Valganciclovir

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Nasopharyngeal Neoplasms; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Neoplasms by Site; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Disease Attributes; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Ganciclovir; Acyclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Cheng-Lung Hsu, Physican

  Chang Gung Memorial Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cheng-Lung Hsu, Physican

CONTACT

(886)3-3281200; hsu2221@cgmh.org.tw

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 7, 2016
• First Posted: May 4, 2016
• Study Start: May 1, 2016
• Primary Completion: June 1, 2017
• Last Updated: May 16, 2016

Record last verified: 2016-03

Locations

TW (1)