Primary:The primary objective is to determine the safety and tolerability of the combination treatment, i.e. GCb, VPA and GCV, by evaluation of adverse events (AE*s) serious adverse events (SAE*s) and all clinically significant changes in clinical…
ID
Source
Brief title
Condition
- Other condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Health condition
Uitbehandeld Nasopharynxcarcinoom
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint:
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
Analysis 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
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.
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.
Background 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).
Study objective
Primary:
The primary objective is to determine the safety and tolerability of the
combination treatment, i.e. GCb, VPA and GCV, by evaluation of adverse events
(AE*s) serious adverse events (SAE*s) and all clinically significant changes in
clinical laboratory values.
Secondary:
* To explore 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 oral GCV
* Clinical response
* Biological effect of the combination of GCb, VPA and GCV
* Monitoring of EBV specific immune responses (i.e. T & B-cell responses)
during treatment
Study design
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.
Study burden and risks
Patients have to be in day care on day 1 and 8 for iv administration of
Gemcitabine.
Patients have to return to the hospital every week for physical examination and
blood sampling. Every 2 weeks patients will receive a non invasive brush
sampling if tumour is accessible in the nasopharynx. Every twelve weeks
patients will have a tumour assessment by MRI and/or CT-scan according to the
RECIST criteria.
The suspected side effects of the medication at doses given are low and since
there is no proper treatment available for these patients and this treatment
has a theoretical beneficial potential we assume a tolerable risk for toxicity
for the participating patients.
Plesmanlaan 121
1066CX Amsterdam
NL
Plesmanlaan 121
1066CX Amsterdam
NL
Listed location countries
Age
Inclusion criteria
• 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.
• Confirmed EBV positive NPC
• Measurable disease, according to RECIST criteria
• WHO PS 0-2
• 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).
• Age 18-70 years
• Signed written informed consent before any study related activities are carried out
• Expected adequacy of follow-up
Exclusion criteria
• Active infection (infection requiring IV antibiotics), including active tuberculosis, and known and declared HIV.
• Pregnancy (absence confirmed by serum or urine β-HCG test) or lactation period
• Concurrent treatment with any other anti-cancer therapy.
• 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.
• Current active hepatic or biliary disease (with exception of Gilbert*s syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
• 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.)
• 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.
• 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
• Legal incapacity
• History of malabsorption syndrome or other disease that could significantly affect absorption of drugs
• Systemic steroids within 2 weeks prior to study treatment
• Myocardial infarction or cerebrovascular accident (CVA) within 6 months prior to study treatment
• Patients who have known hypersensitivity to the study medication
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-022444-20-NL |
| CCMO | NL33500.031.10 |