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
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.
- Number of patients: total 18 patients are needed
- 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.
- Chemotherapy regimen: Gemcitabine (GEM, TTY) + Valproic acid (VPA, generic medicine) for viral activation + Valganciclovir (VGC, Roche) for antiviral medication
- This treatment cycle of 28 days was repeated maximum 6 times. (Q4wks/cycle, max: 6 cycles)
(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:
- primary: to find the best combination of these 3 drugs in recurrent/metastatic NPC patients.
- 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|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||18 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
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.
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
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
- 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):
- ≥Grade 4 neutropenia >5 days;
- ≥Grade 4 thrombopenia lasting ≥7 days;
- ≥Grade 3 anemia;
- ≥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;
- any ≥Grade 3 non-hematologic toxicity with exception of nausea and vomiting, alopecia, drug-related fever;
- ≥Grade 3 serum creatinine;
- 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.
- Safety and tolerability assessed by adverse events, serious adverse events [ Time Frame: 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 [ Time Frame: 3~6 months in treatment, and 3~6 months in followed-up ]
- 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.
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
|Contact: Cheng-Lung Hsu, Physican||(886)3-3281200 ext firstname.lastname@example.org|
|Chang-Gung Memorial Hospital, Linkou||Recruiting|
|Taoyuan, Taiwan, 333|
|Contact: Cheng-Lung Hsu, PhD +886-3-3281200 ext 8684 email@example.com|
|Principal Investigator:||Cheng-Lung Hsu, Physican||Chang Gung Memorial Hospital|