EBV Lytic Reactivation Therapy Combined With PD-1 Antibody in Recurrent/Metastatic Nasopharyngeal Carcinoma

Official title

Efficacy and Safety of EBV Lytic Reactivation Therapy Combined With PD-1 Antibody in Recurrent/Metastatic Nasopharyngeal Carcinoma: a Single-center, Single-arm Phase II Trial

Overview

Nearly all undifferentiated nasopharyngeal carcinoma (NPC) are associated with the Epstein-Barr Virus (EBV), which typically remains in a latent, non-immunogenic state within tumor cells. By combining EBV lytic induction strategy with standard chemo-immunotherapy, this study aims to create a synergistic anti-tumor effect and improve clinical outcomes for patients with recurrent/metastatic NPC (r/m NPC). This is a phase II, single-center, single-arm clinical trial designed to evaluate the efficacy and safety of a novel combination therapy in patients with r/m EBV-positive NPC.

Detailed description

Rationale: Epstein-Barr virus (EBV) is clonally present in nearly all undifferentiated nasopharyngeal carcinoma (NPC) tumor cells, particularly in endemic regions. In most cases, EBV remains in a latent state, expressing only a limited set of non-immunogenic proteins, which facilitates immune evasion by tumor cells. Chemotherapeutic agents such as gemcitabine and cisplatin can induce the EBV lytic cycle, activate valganciclovir hydrochloride, thereby enabling the selective killing of EBV-infected tumor cells. This strategy may act synergistically with immunotherapy. Early-phase clinical studies have demonstrated the safety and potential efficacy of this approach; however, larger-scale studies are required to confirm these findings.

Study Objectives: The primary objectives of this clinical trial are: 1.To assess the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS) in patients receiving chemotherapy combined with valganciclovir hydrochloride and PD-1 antibody. 2.To evaluate the safety profile, including acute and chronic toxicities.

Study Design and Treatment Regimen: Patients with histologically confirmed EBV-positive, recurrent or metastatic NPC will be enrolled. Patients will receive 4 to 6 cycles of gemcitabine, cisplatin, and PD-1 antibody, with oral administration of valganciclovir hydrochloride tablets during the first 3 cycles. Following completion of the 4 to 6 cycles, patients will continue PD-1 antibody maintenance therapy for up to two years or until disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of informed consent, or death.

Interventions

• Drug Valganciclovir Hydrochloride Tablets
  Valganciclovir hydrochloride tablets will be administered at 900 mg twice daily from day 1 to day 14, followed by 450 mg twice daily from day 15 to day 20, for a total of 3 cycles.
• Drug gemcitabine, cisplatin, and PD-1 antibody
  Gemcitabine 1000 mg/m² will be administered intravenously on days 1 and 8; cisplatin 80 mg/m² intravenously on day 1; and PD-1 antibody intravenously on day 1. Each cycle is 21 days in duration, and treatment will be administered for a total of 4 to 6 cycles. Following completion of the 4 to 6 cycles, patients will continue PD-1 antibody maintenance therapy (every 3 weeks) for up to two years or until disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal

Primary outcome measures

• Objective Response Rate, ORR [Time frame: From enrollment to the end of treatment. Up to 2 approximately years.]

Secondary outcome measures (5)

• Disease Control Rate，DCR [Time frame: From enrollment to the end of treatment. Up to 2 approximately years.]
• Progression-free Survival, PFS [Time frame: 1 years; 2 years; 5 years;]
• Duration of Response, DoR [Time frame: From enrollment to disease progression. Up to 2 approximately years.]
• Overall Survival, OS [Time frame: 1 years; 2 years; 5 years]
• Incidence rate of acute and late adverse events (AEs) [Time frame: From enrollment to the end of follow-ups. Up to 2 approximately years.]

Eligibility criteria

Inclusion criteria

• Patients must voluntarily participate and provide written informed consent.
• Histologically or cytologically confirmed recurrent or metastatic nasopharyngeal carcinoma (NPC) at enrollment, with positive EBERs by pathological immunohistochemistry.
• Metastatic NPC includes both newly diagnosed metastatic disease and metastatic disease after failure of first-line therapy, as well as recurrent NPC not amenable to local regional treatment, with confirmed metastatic or recurrent disease and no prior treatment after diagnosis.
• Age ≥ 18 years and ≤ 75 years, of any sex.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Expected survival time ≥ 3 months.
• Baseline plasma EBV DNA > 0 copies/mL.
• Adequate organ function confirmed by the following criteria (no blood component transfusions or use of hematopoietic growth factors within 2 weeks prior to study treatment initiation):
• Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L; platelet count ≥ 100 × 10\^9/L; hemoglobin ≥ 90 g/L. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated creatinine clearance (CrCl) ≥ 60 mL/min . Total bilirubin (TBil) ≤ 1.5 × ULN; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (for patients with liver metastases, TBil ≤ 3 × ULN; AST and ALT ≤ 5 × ULN). Serum albumin ≥ 28 g/L.

Exclusion criteria

• History of severe hypersensitivity reactions to other monoclonal antibodies or to any component of PD-1 inhibitors.
• Receipt of radiotherapy, biological therapy (e.g., tumor vaccines, cytokines, or growth factors), or other immunotherapy (excluding PD-1 and PD-L1 inhibitors), or any other anti-tumor treatment within 28 days or 5 half-lives prior to the first dose of study drug, whichever is shorter.
• Prior treatment targeting Epstein-Barr virus (EBV) specifically.
• History of any Grade ≥3 bleeding event, as defined by CTCAE v5.0, within 4 weeks prior to screening, or patients deemed at high risk of bleeding by the investigator.
• Presence of necrotic lesions within 4 weeks prior to screening, with high risk of major hemorrhage as judged by the investigator.
• Known congenital or acquired immunodeficiency (e.g., HIV-positive individuals).
• Requirement for systemic corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive agents within 14 days prior to initiation of study treatment.
• History of active tuberculosis (TB). Suspected active TB must be excluded through chest X-ray, sputum examination, and clinical assessment of signs and symptoms.
• Patients with HBV DNA ≥1000 copies/mL. Patients with positive hepatitis C antibody results may only be enrolled if polymerase chain reaction (PCR) testing confirms HCV RNA negativity.
• Pregnant or breastfeeding women, or women of childbearing potential not using effective contraception.
• History of other malignancies, except for adequately treated basal cell carcinoma or carcinoma in situ of the cervix.
• Uncontrolled cardiovascular conditions, including but not limited to: Heart failure with NYHA classification ≥2; Unstable angina; Myocardial infarction within the past year; Supraventricular or ventricular arrhythmias requiring treatment or intervention.
• Significant impairment of cardiac, hepatic, pulmonary, renal, or bone marrow function.
• Severe and uncontrolled medical illnesses or infections.
• Concurrent participation in another clinical trial or use of another investigational agent.
• Refusal or inability to sign informed consent.
• Any other contraindications to study treatment as determined by the investigator.
• Individuals with personality disorders or psychiatric conditions, and those lacking or having limited legal capacity to provide consent.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Sun Yat-sen Universitty Cancer Center — Guangzhou

Publications

• Ghosh SK, Perrine SP, Williams RM, Faller DV. Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents. Blood. 2012 Jan 26;119(4):1008-17. doi: 10.1182/blood-2011-06-362434. Epub 2011 Dec 7. PMID 22160379
• Perrine SP, Hermine O, Small T, Suarez F, O'Reilly R, Boulad F, Fingeroth J, Askin M, Levy A, Mentzer SJ, Di Nicola M, Gianni AM, Klein C, Horwitz S, Faller DV. A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies. Blood. 2007 Mar 15;109(6):2571-8. doi: 10.1182/blood-2006-01-024703. Epub 2006 Nov 21. PMID 17119113
• Wu M, Hau PM, Li L, Tsang CM, Yang Y, Taghbalout A, Chung GT, Hui SY, Tang WC, Jillette N, Zhu JJ, Lee HHY, Kong EL, Chan MSA, Chan JYK, Ma BBY, Chen MR, Lee C, To KF, Cheng AW, Lo KW. Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers. Nat Commun. 2024 May 3;15(1):3729. doi: 10.1038/s41467-024-48031-8. PMID 38702330
• Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, Li J, Shi Y, Jin F, Xu R, Pan J, Qu S, Li P, Hu C, Liu YC, Jiang Y, He X, Wang HM, Lim WT, Liao W, He X, Chen X, Wang S, Yuan X, Li Q, Lin X, Jing S, Chen Y, Lu Y, Hsieh CY, Yang MH, Yen CJ, Samol J, Luo X, Wang X, Tang X, Feng H, Yao S, Keegan P, Xu RH. Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 PMID 38015220

Identifiers

NCT: NCT07138989 · 2025-FXY-184

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗