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

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ClinicalTrials.gov Identifier: NCT02761291
Recruitment Status : Unknown
Verified March 2016 by Chang Gung Memorial Hospital.
Recruitment status was:  Recruiting
First Posted : May 4, 2016
Last Update Posted : May 16, 2016
Sponsor:
Collaborator:
TTY Biopharm
Information provided by (Responsible Party):
Chang Gung Memorial Hospital

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. 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.


Condition or disease Intervention/treatment Phase
Nasopharyngeal Carcinoma Drug: Gemcitabine Drug: Valproic acid Drug: Valganciclovir Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Cytolytic Viral Activation Therapy (CVAT) for Recurrent/Metastatic Nasopharyngeal Carcinoma
Study Start Date : May 2016
Estimated Primary Completion Date : June 2017


Arm Intervention/treatment
Experimental: gemcitabine dose escalation
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
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.
Other Name: Gemmis

Drug: Valproic acid
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.
Other Name: Depakine

Drug: Valganciclovir
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.
Other Name: Valcyte




Primary Outcome Measures :
  1. Number of participants suffered dose limiting toxicity (DLT) that are related to this treatment [ Time Frame: The first treatment cycle (1~28 days approximately) ]

    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.


Secondary Outcome Measures :
  1. Safety and tolerability assessed by adverse events, serious adverse events [ Time Frame: 3~6 months ]
  2. 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 [ Time Frame: 3~6 months in treatment, and 3~6 months in followed-up ]
  3. EB virus DNA load in plasma [ Time Frame: 3~6 months in treatment, and 3~6 months in followed-up ]
    The plasma EB virus DNA load will be check by real-time quantitative polymerase chain reaction (PCR). These data will be collected every months when subjects enter this trial and finish their final treatment cycle one weeks, 3 months, and/or 6 months later. These data will be used to supplementary data for tumor status assessment.



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Ages Eligible for Study:   20 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Have the ability to understand and willingness to sign a written informed consent document
  2. 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
  3. Biopsy confirmed belong to World Health Organization classification of nasopharyngeal carcinoma type II or type III
  4. 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
  5. 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
  6. The daily performance status ECOG ≤ 2 points

Exclusion Criteria:

  1. Pregnancy or breast-feeding women, and plans within six months of pregnancy
  2. 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
  3. With insomnia, anxiety or spiritual concerns, or are receiving mental illness treatment
  4. Has been diagnosed with a second cancer, except to basal cell carcinoma
  5. 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
  6. Patients with creatinine clearance rate <40 ml/min

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02761291


Contacts
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Contact: Cheng-Lung Hsu, Physican (886)3-3281200 ext 8684 hsu2221@cgmh.org.tw

Locations
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Taiwan
Chang-Gung Memorial Hospital, Linkou Recruiting
Taoyuan, Taiwan, 333
Contact: Cheng-Lung Hsu, PhD    +886-3-3281200 ext 8684    hsu2221@cgmh.org.tw   
Sponsors and Collaborators
Chang Gung Memorial Hospital
TTY Biopharm
Investigators
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Principal Investigator: Cheng-Lung Hsu, Physican Chang Gung Memorial Hospital

Publications of Results:
Other Publications:

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Responsible Party: Chang Gung Memorial Hospital
ClinicalTrials.gov Identifier: NCT02761291     History of Changes
Other Study ID Numbers: 104-4750A
First Posted: May 4, 2016    Key Record Dates
Last Update Posted: May 16, 2016
Last Verified: March 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Chang Gung Memorial Hospital:
Nasopharyngeal carcinoma
EB virus
metastasis
recurrence
cytolytic viral activation therapy
gemcitabine
valproic acid
ganciclovir
valganciclovir
Additional relevant MeSH terms:
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Nasopharyngeal 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
Carcinoma
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Gemcitabine
Valganciclovir
Valproic Acid
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anticonvulsants
GABA Agents
Neurotransmitter Agents