EPstein-barr Virus DNA Response to Systemic Therapy for Treatment Adaptation in High Risk NPC (EP-STAR) (EP-STAR)

Epstein-Barr Virus DNA to Systemic Therapy for Treatment Adaptation in High Risk Nasopharyngeal Carcinoma (EP-STAR Trial) A Phase II, Multi-center, Biomarker-guided, Umbrella Trial

The investigators aim to investigate whether incorporating on-treatment EBV DNA surveillance for monitoring tumor responses to treatment and for guiding individuliased treatment adaptation can improve prognosis in nasopharyngeal carcinoma patient . For patients with detectable EBV DNA after one cycle of IC, which then drops to undetectable levels during the following IC cycles (intermediate responders/intermediate relapse risk), the investigators aim to investigate whether additional adjuvant metronomic capecitabine would benefit this subgroup. For patients with detectable EBV DNA after three cycles of IC or with EBV DNA bounce during the induction phase (insensitive to IC/high relapse risk), the investigators aim to investigate whether concurrent administration of anti-PD-1 therapy during the following treatment phases (including concurrent phase and adjuvant phase) can benefit this subgroup.

Study Overview

• Status: Active, not recruiting
• Conditions: Nasopharyngeal Carcinoma
• Intervention / Treatment: Drug: Capecitabine; Drug: sintilimab

Detailed Description

Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer characterized by an extremely unbalanced global distribution. The highest incidence is observed in endemic regions, such as southern China and Southeast Asia, with an age-standardized rate of 3.0 per 100,000 in China to 0.4 per 100,000 in Caucasian populations. The fast progress of modern imaging and the application of intensity-modulated radiotherapy (IMRT) has improved the local control rate significantly. Distant metastasis has become the major cause of treatment failure.

The 2018 National Comprehensive Cancer Network (NCCN) guideline recommends concurrent chemoradiotherapy (CCRT) ± induction chemotherapy (IC)/adjuvant chemotherapy (AC) as the standard treatment for stage II-IVa disease (category 2A). While it is worth noting that there is extensive heterogeneity among patients with NPC, and even among patients with the same disease stage, the risk of relapse varies. More importantly, patients can have differing sensitivity to RT and chemotherapy. The abovementioned reasons result in over-treatment in some patients with relatively low relapse risk; intensive treatments lead to unnecessary toxicities, and greatly affect quality of life (QoL). On the other hand, the current treatment strategy may be not optimal for patients with high relapse risk or who are not sensitive to traditional chemoradiotherapy. Therefore, there is an urgent need for identifying and applying promising biomarkers, real-time monitoring of patient responses to treatment, predicting relapse risk, and guiding real-time treatment adaptation for individualized therapy.

The investigators aim to investigate whether incorporating on-treatment EBV DNA surveillance for monitoring tumor responses to treatment and for guiding individuliased treatment adaptation can improve prognosis in nasopharyngeal carcinoma patient . For patients with detectable EBV DNA after one cycle of IC, which then drops to undetectable levels during the following IC cycles (intermediate responders/intermediate relapse risk), the investigators aim to investigate whether additional adjuvant metronomic capecitabine would benefit this subgroup. For patients with detectable EBV DNA after three cycles of IC or with EBV DNA bounce during the induction phase (insensitive to IC/high relapse risk), the investigators aim to investigate whether concurrent administration of anti-PD-1 therapy during the following treatment phases (including concurrent phase and adjuvant phase) can benefit this subgroup.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat-Sen University Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Newly diagnosed, pathologically proven World Health Organization (WHO) type II/III untreated LANPC;
2. LANPC (except T3N0, according to the 8th edition of the AJCC/UICC clinical staging system);
3. Age at diagnosis: 18-65 years;
4. Eastern Cooperative Oncology Group (ECOG) score: 0-1
5. Receiving recommended three cycles of induction chemotherapy (IC) (gemcitabine-cisplatin [GP] regimen);
6. Pre-treatment and post-IC1 cell-free Epstein-Barr virus (cfEBV) DNA > 0 copy/mL; systemic cfEBV DNA monitoring during IC phase for risk stratification;
7. Normal hematic, liver, and kidney function: hemoglobin (HG) > 90 g/L; neutrophil > 1.5 × 109/L; platelet > 100 × 109/L; total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 × ULN; alkaline phosphatase (ALP) ≤ 2.5 × ULN; creatinine clearance (Ccr) ≥ 60 mL/min;
8. Female subjects capable of becoming pregnant agree to use reliable contraceptive measures from screening to 1 year after treatment;
9. Patients will be required to sign informed consent forms and be willing and able to comply with the requirements for visits, treatment, laboratory tests, and other research requirements stipulated in the research schedule.

Exclusion Criteria:

1. Receiving surgery, target therapy, and/or immunotherapy during or before induction phase;
2. Hepatitis B surface antigen-positive [HBsAg(+)],hepatitis B virus (HBV) DNA > 1×103 copy/mL; hepatitis C virus (HCV) antibody(+);
3. Other previous or concurrent malignant tumors, except adequately treated non-melanoma skin cancer, cervical carcinoma in situ, and thyroid papillary cancer;
4. Pregnant or lactating women (a pregnancy test should be considered for fertile women with an active sex life);
5. Previously treated with radical radiotherapy (RT), except non-melanoma skin cancers outside intended RT treatment volume;

6. Uncontrolled heart disease, e.g.: 1) Heart failure, Hew York Heart Association (NYHA) level ≥ 2; 2) unstable angina; 3) myocardial infarction in the past 1 year; 4) supraventricular or ventricular arrhythmia requiring treatment or intervention;

   *For patients recruited to Arm II, the additional exclusion criteria are:

7. Active, known, or suspected autoimmune disease (including, but not limited to, uveitis, enteritis, hepatitis, pituitary, nephritis, vasculitis, hyperthyroidism, hypothyroidism, and asthma requiring bronchiectasis). Exceptions are type I diabetes mellitus, hypothyroidism requiring hormone replacement therapy, and skin disorders requiring no systemic treatment (e.g., vitiligo, psoriasis, alopecia);
8. Received live vaccine within 1 month before treatment initiation;
9. Allergy to macromolecular protein preparations, or any component of sintilimab;
10. Human immunodeficiency virus (HIV)-positive or diagnosed with Acquired Immune Deficiency Syndrome (AIDS).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive GP IC + IMRT concurrent with cisplatin chemotherapy + capecitabine AC. All patients will receive concurrent cisplatin (100 mg/m2) every 3 weeks, in a total of three cycles. All patients will receive low-dose metronomic capecitabine (650 mg/m2 bid, oral, d1-21, q3w) until disease progression, or intolerable toxicity or 6 months.	Drug: Capecitabine; Investigate whether capecitabine would be able to improve prognosis in patients at intermediate risk groups
Experimental: Arm II; Patients receive GP IC + IMRT concurrent with cisplatin chemotherapy and anti-PD-1 therapy (sintilimab) + anti-PD-1 therapy (sintilimab) AC. All patients will receive concurrent cisplatin (100 mg/m2) and sintilimab (200 mg, IV drop 30-60 min) every 3 weeks in a total of three cycles. All patients will receive adjuvant anti-PD-1 therapy (sintilimab, 200 mg, IV drop 30-60 min, q3w) in a total of nine cycles until disease progression, or intolerable toxicity or 6 months.	Drug: sintilimab; Investigate whether capecitabine would be able to improve prognosis in patients at high risk groups

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Failure-free survival	FFS will be measured from the day of enrollment until treatment failure, death from any cause, or the last follow-up visit, whichever occurred first.	2 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall survival	measured from the day of enrollment until death due to any cause, or the last follow-up visit.	2 year
Distant metastasis failure-free survival	measured from the day of enrollment until death until distant metastasis , or the last follow-up visit.	2 year
Locoregional failure-free survival	measured from the day of enrollment until death until local and/or regional recurrence, or the last follow-up visit.	2 year
Adverse events	The incidence of immune-related and other adverse events	up to 5 years
Patient reported quality-of-life score	Patient reported quality of life would be evaluated using the Quality of Life Questionnaire-Core 30 module (QLQ-C30)	up to 2 years
Biomarker analysis	Exploratory biomarker analysis that would be able to predict patient treatment benefits, for example PD-L1 expression, tumor mutational burden, etc.	Through study completion

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Wuzhou Red Cross Hospital; First People's Hospital of Foshan; National Cancer Centre, Singapore
• Investigators: Principal Investigator: Ying Sun, M.D., Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: August 24, 2019
• First Submitted That Met QC Criteria: August 26, 2019
• First Posted (Actual): August 28, 2019

Study Record Updates

• Last Update Posted (Estimated): June 19, 2023
• Last Update Submitted That Met QC Criteria: June 16, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: nasopharyngeal carcinoma; EBV DNA; Biomarker-guided; Treatment adaptation
• Additional Relevant MeSH Terms: Virus Diseases; Infections; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; DNA Virus Infections; Tumor Virus Infections; Herpesviridae Infections; Nasopharyngeal Neoplasms; Carcinoma; Nasopharyngeal Carcinoma; Epstein-Barr Virus Infections; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine
• Other Study ID Numbers: B2019-185-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Currently, there is no plan to make individual participant data (IPD) available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No