Ignite Creation Date:
2024-05-06 @ 8:34 AM
Last Modification Date:
2024-10-26 @ 12:01 PM
Study NCT ID:
NCT02761291
Status:
UNKNOWN
Last Update Posted:
2016-05-16
First Post:
2016-04-07
Brief Title:
Study of Cytolytic Viral Activation Therapy CVAT for RecurrentMetastatic Nasopharyngeal Carcinoma
Sponsor:
Chang Gung Memorial Hospital
Organization:
Chang Gung Memorial Hospital
Study Overview
Official Title:
Phase I Study of Cytolytic Viral Activation Therapy CVAT for RecurrentMetastatic Nasopharyngeal Carcinoma
Status:
UNKNOWN
Status Verified Date:
2016-03
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Nasopharyngeal carcinoma NPC is an Epstein-Barr virusEBV 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 criteria1 used as 2nd line regimen in recurrencemetastasis NPC patients with tissue proved of World Health Organization WHO type II or type III2 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 Q4wkscycle max 6 cycles
5 Dosage
1 GEM 600 800 1000 1250 mgm2 D1 D8 intravenously 2 VPA 125 mgkgday D114 per os 3 VGC 2-3 x 450 mgday D915 per os 6 Objectives
1 primary to find the best combination of these 3 drugs in recurrentmetastatic 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
1 Number of patients total 18 patients are needed
2 Inclusion criteria1 used as 2nd line regimen in recurrencemetastasis NPC patients with tissue proved of World Health Organization WHO type II or type III2 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 Q4wkscycle max 6 cycles
5 Dosage
1 GEM 600 800 1000 1250 mgm2 D1 D8 intravenously 2 VPA 125 mgkgday D114 per os 3 VGC 2-3 x 450 mgday D915 per os 6 Objectives
1 primary to find the best combination of these 3 drugs in recurrentmetastatic 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
Detailed Description:
1 Introduction to investigational treatments and other study treatments
11 Overview of gemcitabine Gemcitabine 2929-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 06-12 gm2 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 36 and 51 months 5 In combination chemotherapy with cisplatin the OR rate 427 to 73 had been reported and median PFS were 56 to 106 months 6 In combined with oxaliplatin the OR rate was 561 and median PFS was 9 months 6 In combined with vinorelbine OR rate 36 to 377 had been reported and median PFS were 52 to 56 months In multiple drugs combination with carboplatin paclitaxel 5-Fluoro-UracilLeucoVorin 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
12 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
Valproic acid VPA as a HDAC inhibitor can specifically target at class I a I b and II a HDACs 8 VPA also down regulates expression of proteins essential for chromatin maintenance Structural Maintenance of chromatin SMC DNA methyl transferase-1 DNMT1 and heterochromatin protein-1 HP1 9 VPA had been shown to induce histone 3 methylation which would increase transcriptional activity 8 VPA had been shown some anticancer effect major through its HDAC inhibitor in single agent or combined with other anticancer medication including myeloid and lymphoid malignancies breast cancer prostate cancer and NPC 10-13 Long-term VPA treatment may cause central nervous system CNS dysfunction liver toxicity and coagulopathy including thrombocytopenia and platelet dysfunction 7
13 Ganciclovir GCV and Valganciclovir VGC GCV was an antiviral agent had been used in treatment or prophylaxis of cytomegalovirus infection in solid organ transplantation recipients or bone marrow transplantation 14 GCV is a synthetic analogue of 2-deoxy-guanosine and can be phosphorylated to ganciclovir triphosphate a competitive inhibitor of deoxyguanosine triphosphate dGTP incorporation into DNA and preferentially inhibits viral DNA polymerases more than cellular DNA polymerases by viral and cell kinase In addition ganciclovir triphosphate serves as a poor substrate for chain elongation thereby disrupting viral DNA synthesis by a second route 15
VGC a valyl ester prodrug of GCV had a high oral bioavailability of about 60 with similar efficacy of GCV in management of cytomegalovirus infection 16 The most common side effect of IV GCV is fever and leukopenia 16
14 Combination of GEM VPA and GCV in NPC treatment In EBV-related malignancy antiviral drugs exhibit no direct effect on cancer cell except when used combined with epigenetically active agents 17 18 Recently Wildeman et al had shown some efficacy by combining chemotherapy of GEM with VPA and GCV in control of locally advancedmetastatic NPC patients 13 In this article both GEM and VPA could shift EBV from latent phase into lytic phase and had synergetic effect when combined used Further adding GCV in this regimen could suppress virion formation The combination therapy had been tested in three locally advancedmetastatic NPC patients showing promising results with tumor regressingstable in image and plasma EBV DNA load monitoring with few side effects Similar manageable side effects of these three drugs combined treatment were also proved by Stoker et al 19 These results encouraged us to develop a more practical regimen in this trial
2 Test products dosage and mode of administration
21 Chemotherapy regimen Gemcitabine Gemmis injection200 mg GEM TTY Valproic acid Depakine gastro-resistant tablet200 mg VPA Sanofi for viral activation Valganciclovir Valcyte film-coated tablets450 mg VGC Roche for antiviral medication
22 Dosage GEM 6001250 mgm2 D1 D8 intravenously VPA 125 mgkgday D114 per os VGC 23 x 450mgday D915 per os
1 This treatment cycle of 28 days will be repeated maximum 6 times Q4wkscycle max 6 cycles
2 Four dosage of GEM combined with fixed dosage of VPA and VGC will be tested
3 The rationale of seven days treatment duration of VGC come from A 7 days treatment duration of valacyclovir in herpes zoster in immunocompetent patients 20 B overlap side effect of myelosuppression between GEM and VGC13
4 Efficient dose intensity chemotherapy gemcitabine is essential in this three combined drugs regimen 21 and this trial will be started with dose level 0 Gemcitabine 800 mgm2
23 Concomitant treatment
231 Permitted The related treatment for relieve symptoms caused from tumor
232 Prohibited
1 Radiation therapy operation and other chemotherapy for eradicating tumor
2 Valganciclovir concomitant with Imipenem-cilastatin could result in convulsion with zidovudine could result in neutropenia with Probenecid would increase toxicity of ganciclovir
3 Co-administration of valproate with amitryptylinenortryptyline and warfarin need to be adjusted if necessary
4 Co-administration of valganciclovir with didanosine Mycophenolate mofetil and bone marrow suppression drugs eg dapsone pentamidine flucytosine vincristine vinblastine adriamycin amphotericin B nucleoside analogues hydroxyurea would need to be monitored more seriously because of their toxicity might increase
5 All other drugs prohibited co-administration with valproic acid absolutely
3 Duration of treatment This treatment cycle of 28 days will be repeated maximum 6 times Q4wkscycle max 6 cycles A standard 3 3 phase I dose escalation study design was used 22 A minimum of three evaluable patients were to be treated at each dose level According to Worst Toxicity CTCAE v403 Grade and FDA indication of gemcitabine the dose limiting toxicity DLT of this trial was determined in the first treatment cycle
In the absence of DLT patients were enrolled in the next dose level If 1 of three patients had a DLT the cohort was expanded to include six patients If 2 patients experienced DLT maximum tolerated dose MTD was exceeded and further enrollment at that dose level was stopped MTD was defined as the highest dose level at which 1 of 6 patients experienced a DLT Only DLT that occurred during the first treatment cycle were used to determine the MTD
4 Patient examination and re-evaluation Laboratory data of complete blood count CBCdifferential count DC creatinine alanine aminotransferase ALT will be routine checked every weeks during the first 3 treatment cycles During all treatment courses if grade 4 neutropenia or grade 4 thrombocytopenia attacked the laboratory will be checked every 3 days until recovered to pre-treatment baseline Around 70 responsive and stable cases could be enrolled in the 4th treatment cycle will be routine checked the laboratory data before gemcitabine administration Plasma EBV DNA copies number will be monitored before each cycle treatment Systemic re-evaluation will be performed after every three cycles treatment Re-evaluation including physical examination image studies including CTMRI for head and neck area chest x-ray abdominal echo and Gallium whole body tumor scan and blood exam including complete CBC count biochemical profile and plasma EBV DNA copies number
11 Overview of gemcitabine Gemcitabine 2929-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 06-12 gm2 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 36 and 51 months 5 In combination chemotherapy with cisplatin the OR rate 427 to 73 had been reported and median PFS were 56 to 106 months 6 In combined with oxaliplatin the OR rate was 561 and median PFS was 9 months 6 In combined with vinorelbine OR rate 36 to 377 had been reported and median PFS were 52 to 56 months In multiple drugs combination with carboplatin paclitaxel 5-Fluoro-UracilLeucoVorin 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
12 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
Valproic acid VPA as a HDAC inhibitor can specifically target at class I a I b and II a HDACs 8 VPA also down regulates expression of proteins essential for chromatin maintenance Structural Maintenance of chromatin SMC DNA methyl transferase-1 DNMT1 and heterochromatin protein-1 HP1 9 VPA had been shown to induce histone 3 methylation which would increase transcriptional activity 8 VPA had been shown some anticancer effect major through its HDAC inhibitor in single agent or combined with other anticancer medication including myeloid and lymphoid malignancies breast cancer prostate cancer and NPC 10-13 Long-term VPA treatment may cause central nervous system CNS dysfunction liver toxicity and coagulopathy including thrombocytopenia and platelet dysfunction 7
13 Ganciclovir GCV and Valganciclovir VGC GCV was an antiviral agent had been used in treatment or prophylaxis of cytomegalovirus infection in solid organ transplantation recipients or bone marrow transplantation 14 GCV is a synthetic analogue of 2-deoxy-guanosine and can be phosphorylated to ganciclovir triphosphate a competitive inhibitor of deoxyguanosine triphosphate dGTP incorporation into DNA and preferentially inhibits viral DNA polymerases more than cellular DNA polymerases by viral and cell kinase In addition ganciclovir triphosphate serves as a poor substrate for chain elongation thereby disrupting viral DNA synthesis by a second route 15
VGC a valyl ester prodrug of GCV had a high oral bioavailability of about 60 with similar efficacy of GCV in management of cytomegalovirus infection 16 The most common side effect of IV GCV is fever and leukopenia 16
14 Combination of GEM VPA and GCV in NPC treatment In EBV-related malignancy antiviral drugs exhibit no direct effect on cancer cell except when used combined with epigenetically active agents 17 18 Recently Wildeman et al had shown some efficacy by combining chemotherapy of GEM with VPA and GCV in control of locally advancedmetastatic NPC patients 13 In this article both GEM and VPA could shift EBV from latent phase into lytic phase and had synergetic effect when combined used Further adding GCV in this regimen could suppress virion formation The combination therapy had been tested in three locally advancedmetastatic NPC patients showing promising results with tumor regressingstable in image and plasma EBV DNA load monitoring with few side effects Similar manageable side effects of these three drugs combined treatment were also proved by Stoker et al 19 These results encouraged us to develop a more practical regimen in this trial
2 Test products dosage and mode of administration
21 Chemotherapy regimen Gemcitabine Gemmis injection200 mg GEM TTY Valproic acid Depakine gastro-resistant tablet200 mg VPA Sanofi for viral activation Valganciclovir Valcyte film-coated tablets450 mg VGC Roche for antiviral medication
22 Dosage GEM 6001250 mgm2 D1 D8 intravenously VPA 125 mgkgday D114 per os VGC 23 x 450mgday D915 per os
1 This treatment cycle of 28 days will be repeated maximum 6 times Q4wkscycle max 6 cycles
2 Four dosage of GEM combined with fixed dosage of VPA and VGC will be tested
3 The rationale of seven days treatment duration of VGC come from A 7 days treatment duration of valacyclovir in herpes zoster in immunocompetent patients 20 B overlap side effect of myelosuppression between GEM and VGC13
4 Efficient dose intensity chemotherapy gemcitabine is essential in this three combined drugs regimen 21 and this trial will be started with dose level 0 Gemcitabine 800 mgm2
23 Concomitant treatment
231 Permitted The related treatment for relieve symptoms caused from tumor
232 Prohibited
1 Radiation therapy operation and other chemotherapy for eradicating tumor
2 Valganciclovir concomitant with Imipenem-cilastatin could result in convulsion with zidovudine could result in neutropenia with Probenecid would increase toxicity of ganciclovir
3 Co-administration of valproate with amitryptylinenortryptyline and warfarin need to be adjusted if necessary
4 Co-administration of valganciclovir with didanosine Mycophenolate mofetil and bone marrow suppression drugs eg dapsone pentamidine flucytosine vincristine vinblastine adriamycin amphotericin B nucleoside analogues hydroxyurea would need to be monitored more seriously because of their toxicity might increase
5 All other drugs prohibited co-administration with valproic acid absolutely
3 Duration of treatment This treatment cycle of 28 days will be repeated maximum 6 times Q4wkscycle max 6 cycles A standard 3 3 phase I dose escalation study design was used 22 A minimum of three evaluable patients were to be treated at each dose level According to Worst Toxicity CTCAE v403 Grade and FDA indication of gemcitabine the dose limiting toxicity DLT of this trial was determined in the first treatment cycle
In the absence of DLT patients were enrolled in the next dose level If 1 of three patients had a DLT the cohort was expanded to include six patients If 2 patients experienced DLT maximum tolerated dose MTD was exceeded and further enrollment at that dose level was stopped MTD was defined as the highest dose level at which 1 of 6 patients experienced a DLT Only DLT that occurred during the first treatment cycle were used to determine the MTD
4 Patient examination and re-evaluation Laboratory data of complete blood count CBCdifferential count DC creatinine alanine aminotransferase ALT will be routine checked every weeks during the first 3 treatment cycles During all treatment courses if grade 4 neutropenia or grade 4 thrombocytopenia attacked the laboratory will be checked every 3 days until recovered to pre-treatment baseline Around 70 responsive and stable cases could be enrolled in the 4th treatment cycle will be routine checked the laboratory data before gemcitabine administration Plasma EBV DNA copies number will be monitored before each cycle treatment Systemic re-evaluation will be performed after every three cycles treatment Re-evaluation including physical examination image studies including CTMRI for head and neck area chest x-ray abdominal echo and Gallium whole body tumor scan and blood exam including complete CBC count biochemical profile and plasma EBV DNA copies number
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None