Phase I Study of Cytolytic Viral Activation Therapy (CVAT) for Recurrent/Metastatic Nasopharyngeal Carcinoma
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Number of participants suffered dose limiting toxicity (DLT) that are related to this treatment
研究概览
简要总结
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)
- 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:
- 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.
详细描述
- Introduction to investigational treatment(s) and other study treatment(s)
1.1 Overview of gemcitabine Gemcitabine (29,29-difluoro 29-deoxycytidine, dFdC) which developed from cytosine arabinoside (Ara-C) is an nucleoside analog used as chemotherapy. It was intended as an antiviral drug in initial, but preclinical testing showed that it killed leukemia cells and a spectrum of solid tumor in vitro. In cell, gemcitabine undergoes complex intracellular conversion to the active forms of nucleotides gemcitabine diphosphate (dFdCDP) and triphosphate (dFdCTP) that will influence DNA synthesis. dFdCTP competes with deoxycytidine triphosphate (dCTP) and dFdCDP is a potent inhibitor of ribonucleoside reductase (1). Gemcitabine is administered by the intravenous route with dose ranges from 0.6-1.2 g/m^2 of body surface area (2), and has been used in a broad spectrum cancer management including lung, breast, pancrease, and bladder (3).
The toxic profile of gemcitabine was major in hematopoietic system especially neutropenia and thrombocytopenia (4). In NPC treatment, gemcitabine had been the focus of several reports, with interesting OR rates in the range of 23-48% and median progression-free survival (PFS) of between 3.6 and 5.1 months (5). In combination chemotherapy with cisplatin, the OR rate 42.7 to 73% had been reported and median PFS were 5.6 to 10.6 months (6). In combined with oxaliplatin, the OR rate was 56.1 % and median PFS was 9 months (6). In combined with vinorelbine, OR rate 36 to 37.7% had been reported and median PFS were 5.2 to 5.6 months. In multiple drugs combination with carboplatin, paclitaxel, 5-Fluoro-Uracil/LeucoVorin, high OR rate with 86% had been reported but with median PFS of 8 months (6). Still these trials were done in small series and lacking randomized large scale phase III trial.
1.2 Valproic acid (VPA) Valproic acid (VPA), a branched short-chain fatty acid, is widely used in clinical as an antiepileptic drug and a mood stabilizer, primarily in the treatment of epilepsy, bipolar disorder, and prevention of migraine headaches (7). The antiepileptic properties of VPA have been attributed to inhibition of Gamma Amino Butyrate (GABA) trans aminobutyrate and of ion channels.
VPA was recently classified among the Histone Deacetylase (HDAC) inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. Chromatin is formed of DNA packaged in nucleosome structures. The condensed form of chromatin (heterochromatin) is inactive in terms of transcription whereas the decondensed form (euchromatin) corresponds to an active form. The histone acetylation leads to relaxation of the nucleosome structure, releasing the DNA and allowing transcription. Inhibition of histone deacetylases (HDACs) promotes decondensed chromatin formation, thereby promoting the expression of genes (7).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Gemcitabine (Drug)
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.
干预措施: Valproic acid (Drug)
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.
干预措施: Valganciclovir (Drug)
结局指标
主要结局
Number of participants suffered dose limiting toxicity (DLT) that are related to this treatment
时间窗: 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.
次要结局
- 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)