|- candidate number||9082|
|- NTR Number||NTR2740|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||8-feb-2011|
|- Secondary IDs||40-41200-98-9069 ZonMw|
|- Public Title||Trial to conduct the safety and efficacy of a new combination of registered medicine for the treatment of advanced Nasopharyngeal Carcinoma (NPC).|
|- Scientific Title||PHASE I-II STUDY OF GEMCITABINE (GCB) AND VALPROIC ACID(VPA) PLUS VALGANCICLOVIR(GCV) IN PATIENTS WITH ADVANCED NASOPHARYNGEAL CARCINOMA(NPC).|
|- ACRONYM||PHASE I-II STUDY OF GCB AND VPA PLUS GCV IN PATIENTS WITH ADVANCED NPC|
|- hypothesis||We aim to use Epstein-Barr Virus (EBV) within nasopharyngeal carcinoma (NPC) tumour cells as therapeutic target. In these cells EBV “hides” in a latent state due to methylation of the viral promoters, expressing only few non-immunogenic viral proteins essential for EBV maintenance and contributing to tumour growth. The cytolytic virus activation (CLVA) therapy activates virus gene expression in tumour cells, thereby improving immune recognition and susceptibility to antiviral therapy. This will be achieved by combined use of an anti-tumour drug (gemcitabine), an anticonvulsant (valproic acid) and an antiviral drug (valganciclovir).|
|- Healt Condition(s) or Problem(s) studied||Advanced Nasopharyngeal Carcinoma, Metastatic Nasopharyngeal Carcinoma|
|- Inclusion criteria||1. Patient has histological confirmed residual, recurrent or metastatic nasopharyngeal carcinoma that has failed conventional curative treatments and deemed incurable, or patient refuses further treatment with conventional methods because of associated morbidity/mortality or private reasons;|
2. Confirmed EBV positive NPC;
3. Measurable disease, according to RECIST criteria;
4. WHO PS 0-2;
5. Minimal acceptable safety laboratory values:
A. ANC of ≥ 1.5 × 109/L;
B. Platelet count of ≥ 100 × 109/L;
C. Haemoglobin level of ≥ 10 g/dL (≥ 6.2 mmol/L) (prior transfusion is permitted);
D. Hepatic function as defined by serum bilirubin ≤ 1.25 times the upper limit of normal (ULN), ALT and AST ≤ 2.5 times the ULN;
E. Renal function as defined by serum creatinine ≤ 1.25 times ULN or creatinine clearance ≥ 50 m/min (by Cockcroft-Gault formula).
6. Age 18-70 years;
7. Signed written informed consent before any study related activities are carried out;
8. Expected adequacy of follow-up.
|- Exclusion criteria||1. Active infection (infection requiring IV antibiotics), including active tuberculosis, and known and declared HIV;|
2. Pregnancy (absence confirmed by serum or urine β-HCG test) or lactation period;
3. Concurrent treatment with any other anti-cancer therapy;
4. Class 3-4 cardiac morbidity, as defined by the New York Heart association Criteria (e.g. uncontrolled or symptomatic congestive heart failure, myocardial infarction within six months prior to the start of study, uncontrolled or symptomatic angina) and any cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient;
5. Current active hepatic or biliary disease (with exception of Gilbert’s syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment);
6. Presence of severe and/or uncontrolled concurrent medical disease (e.g. uncontrolled diabetes mellitus, uncontrolled liver disease, including chronic viral hepatitis judged at risk of reactivation, uncontrolled active infection such as HIV infection, etc.);
7. Concomitant (or within 4 weeks before randomization) administration of any other experimental drug under investigation; chemotherapy or other anti-cancer therapy for the recurrence or metastatic disease; chemotherapy for initial treatment, i.e. chemoradiotherapy, is allowed;
8. Concurrent or previous malignancy of a different tumor type within five years of starting the study except for adequately treated non-melanoma skin cancer or cervical intraepithelial neoplasia;
9. Legal incapacity;
10. History of malabsorption syndrome or other disease that could significantly affect absorption of drugs;
11. Systemic steroids within 2 weeks prior to study treatment;
12. Myocardial infarction or cerebrovascular accident (CVA) within 6 months prior to study treatment;
13. Patients who have known hypersensitivity to the study medication.
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||Single arm|
|- planned startdate ||1-feb-2011|
|- planned closingdate||1-feb-2014|
|- Target number of participants||20|
|- Interventions||Patients will receive VPA given orally on day 1 (12.5 mg/kg/day) during 14 days. GCb (1250 mg/m2) will be given at day 1 and 8 intravenously. At day 9 GCV will be given orally daily till day 22 (3x 450 mg/day). One cycle will last 21 days of medication use and 21 days of no medication use for restoration of the immune system. The second cycle starts 6 week after day one of the first cycle.|
|- Primary outcome||Safety and tolerability endopoints of combination treatment, i.e. GCb, VPA and GCV, will consist of the evaluation of adverse events (AE’s) serious adverse events (SAE’s) and all clinically significant changes in clinical laboratory values. |
|- Secondary outcome||1. Analysis of pharmacokinetic and pharmacodynamic changes during lytic induction therapy. The pharmacokinetic and pharmacodynamic profile of GCb, VPA and GCV. Pharmacokinetic endpoints will consist of parameters such as AUC, Css, Cmax, tmax and t1/2 of i.v. Gemcitabine and oral VPA and GCV in combination;|
2. Analysis of clinical response: Assessment (according to RECIST criteria) of anti-tumor activity will be obtained every 2 cycles (12 weeks) and will be recorded as complete response, partial response, stable disease or progressive disease;
3. Analysis of biological effect of the lytic induction therapy:
In order to evaluate therapy induced changes in EBV antigen presentation specific EBV DNA and RNA profiling methods will be used to accurately monitor EBV-driven gene activation and transcription. In addition, levels and diversity in the humoral immune responses and EBV specific T-cell responses will be assessed during treatment in patients with suitable HLA types by in vitro incubation with EBV specific tetramers.
|- Timepoints||Primary outcome: Maximum of 2 years after finish treatment.|
1. After collection of all samples;
2. Every 12 weeks till 2 years after finish treatment;
3. After collection of all samples.
|- Trial web site||N/A|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES||MD. M. Wildeman|
|- CONTACT for SCIENTIFIC QUERIES||MD. M. Wildeman|
|- Sponsor/Initiator ||ZonMw: The Netherlands Organization for Health Research and Development, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI AVL) |
(Source(s) of Monetary or Material Support)
|ZON-MW, The Netherlands Organization for Health Research and Development, VU University Medical Center|
|- Publications||1. Feng, W., G. Hong, H. Delecluse, and S. Kenney. Lytic induction therapy for Epstein-Barr virus-positive B-cell lymphomas. J.Virol. 2004; p1893-902.|
2. Feng, W. and S. Kenney. Valproic acid enhances the efficacy of chemotherapy in EBV-positive tumors by increasing lytic viral gene expression. Cancer Res. 2006; p8762-69.
3. Braakhuis, B., v. H. Ruiz, V, M. Welters, and G. Peters. Schedule-dependent therapeutic efficacy of the combination of gemcitabine and cisplatin in head and neck cancer xenografts. Eur.J.Cancer 1995; p2335-404.
Tao, Q. and A. Chan. Nasopharyngeal carcinoma: molecular pathogenesis and therapeutic developments. Expert.Rev.Mol.Med. 2007;p1-24.
|- Brief summary||We aim to use Epstein-Barr Virus (EBV) within nasopharyngeal carcinoma (NPC) tumour cells as therapeutic target. In these cells EBV “hides” in a latent state due to methylation of the viral promoters, expressing only few non-immunogenic viral proteins essential for EBV maintenance and contributing to tumour growth. The cytolytic virus activation (CLVA) therapy activates virus gene expression in tumour cells, thereby improving immune recognition and susceptibility to antiviral therapy. This will be achieved by combined use of an anti-tumour drug (gemcitabine), an anticonvulsant (valproic acid) and an antiviral drug (valganciclovir).This is an open-label, single centre phase I-II study non-randomized study to define safety and tolerability of the cytolytic virus activation therapy. In total 20 patients will be included.|
Each treatment cycle will take 6 weeks. For restoration of the immune system treatment will be ended after 6 cycles. After the first 2 cycles (12 weeks) there will be a response evaluation to assess if patients respond to the treatment. In case of stable disease (SD), partial response (PR) or complete response (CR) patient will continue treatment. In case of progressive disease (PD) patient will be withdrawn.
When a responding patient (SD, PR or CR) has a relapse during follow up, re-treatment with lytic therapy will be allowed if the treating physician considers re-treatment the best treatment option.
|- Main changes (audit trail)|
|- RECORD||8-feb-2011 - 19-feb-2011|