Study of Cytolytic Viral Activation Therapy (CVAT) for Recurrent/Metastatic Nasopharyngeal Carcinoma

Description

1. 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 2348% 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).

     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).

     1.3 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).

     1.4 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
     advanced/metastatic 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 advanced/metastatic NPC patients showing promising results
     with tumor regressing/stable 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:

2.1. 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

2.2. Dosage GEM: 600~1250 mg/m^2, D1 & D8, intravenously. VPA: 12.5 mg/kg/day D1~14, per os. VGC: (2~3) x 450mg/day D9~15, per os.

1. This treatment cycle of 28 days will be repeated maximum 6 times. (Q4wks/cycle, 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 VGC(13).
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 mg/m^2)

2.3. Concomitant treatment

2.3.1 Permitted: The related treatment for relieve symptoms caused from tumor.

2.3.2 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 amitryptyline/nortryptyline, and warfarin need to be adjusted if necessary
4. Co-administration of valganciclovir with didanosine, Mycophenolate mofetil, and bone marrow suppression drugs (e.g., 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
6. Duration of treatment: This treatment cycle of 28 days will be repeated maximum 6 times. (Q4wks/cycle, 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 v4.03 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 (CBC)/differential 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 CT/MRI 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.

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