Adjuvant Sintilimab Plus Capecitabine in Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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This randomized clinical trial determining whether Sintilimab plus Capecitabine versus Capecitabine alone can improve the progression-free survival rate of NPC patients with unfavorable response to induction chemotherapy. Patients whose plasma EBV DNA> 0 copy/mL or SD/PD according to RECIST1.1 after two cycles induction chemotherapy will have concurrent chemoradiotherapy. MRI, CT and EBV DNA will be assessed before the end of radiotherapy. After concurrent chemoradiotherapy, eligible patients will be randomized to receive either adjuvant Sintilimab plus Capecitabine or Capecitabine alone.

Detailed Description
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Currently, although NCCN (National Comprehensive Cancer Network) guidelines recommend induction chemotherapy combined with concurrent chemoradiotherapy as IIA level-evidenced treatment for nasopharyngeal carcinoma (NPC), there are still about 20-30% of patients with NPC who experienced recurrence and metastasis after radical treatment. Our previous results showed that patients with plasma Epstein-Barr virus (EBV) DNA > 0 copy/mL or stable disease/progressive disease (SD/PD) after induction chemotherapy had a significantly higher risk of disease progression than patients with plasma EBV DNA=0 copy/mL and complete response/partial response (CR/PR), according to Response Evaluation Criteria in Solid Tumors (RECIST). As for these high-risk patients, the urgent clinical problem to be solved is whether increased adjuvant treatment intensity after concurrent chemoradiotherapy can improve their survival rates. The addition of adjuvant capecitabine to chemoradiotherapy significantly improved survival in patients with NPC, with a manageable safety profile. Sintilimab is a humanized monoclonal antibody against programmed death 1(PD-1). Anti-PD-1 monoclonal antibody showed efficacy and safety in previous studies, however, the efficacy of immunotherapy alone was limited. Several prospective studies have shown that anti-PD-1 monoclonal antibody combined with chemotherapy had a synergistic effect. Based on this, this randomized clinical trial determining whether adjuvant Sintilimab plus Capecitabine versus Capecitabine alone can improve the progression-free survival rate of patients with unfavorable response to induction chemotherapy and may provide new evidence for individualized comprehensive treatment of NPC patients.

Official Title
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A Randomized, Open-Label, Phase II Study to Evaluate the Efficacy and Safety of Sintilimab Plus Capecitabine Versus Capecitabine Alone as Adjuvant Therapy for Patients With Locoregionally Advanced Nasopharyngeal Carcinoma

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Drug: Sintilimab
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed non-keratinizing nasopharyngeal carcinoma, type of WHO II or III. Tumor staged as II-IVa (AJCC 8th,excluding T2N0 disease). Age ≥ 18 years and ≤ 70 years, both genders. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Patients with plasma EBV DNA> 0 copy/mL or PD/SD according to RECIST1.1 after two cycles of induction chemotherapy. Completed protocol-specified curative chemoradiotherapy, including two cycles of induction chemotherapy, intensity-modulated radiotherapy, and concurrent cisplatin chemotherapy( at least 2 cycles of concurrent cisplatin chemotherapy). Completion of the last radiation dose within 1 to 7 days before randomization No progression after prior cCRT Adequate marrow function: neutrocyte count≥1.5×10e9/L, hemoglobin ≥90g/L and platelet count ≥100×10e9/L. Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) ≤2.5×upper limit of normal (ULN), and bilirubin ≤ 1.5×ULN. Adequate renal function: creatinine clearance rate ≥ 60 ml/min (Cockcroft-Gault formula). Patients must be informed of the investigational nature of this study and give written informed consent. Women of childbearing potential (WOCBP) who are sexually active must be willing to adhere to effective contraception during treatment and for 1 year after the last dose of study drug. Men who are sexually active with WOCBP must be willing to adhere to effective contraception during treatment and for 1 year after the last dose of the study drug. Exclusion Criteria: Histologically confirmed keratinizing squamous cell carcinoma (WHO I). Prior malignancy within 5 years, except in situ cancer, adequately treated non-melanoma skin cancer, and papillary thyroid carcinoma. Has received a live vaccine within 30 days before informed consent or will receive a live vaccine in the near future. Is pregnant or breastfeeding. Hepatitis B surface antigen (HBsAg) positive and hepatitis B virus DNA >1×10e3 copies/ml or 200IU/ml Hepatitis C virus (HCV) antibody positive Has active autoimmune disease, except type I diabetes, hypothyroidism treated with replacement therapy, and skin disease that doesn't require systemic treatment (e.g., vitiligo, psoriasis, or alopecia). Has any condition that required systemic corticosteroid (equivalent to prednisone >10mg/d) or other immunosuppressive therapy within 28 days before informed consent. Patients received systemic corticosteroid equivalent to prednisone ≤10mg/d, inhale or topical corticosteroid will be allowed. Has a known history of active TB (bacillus tuberculosis) within 1 year; patients with adequately treated active TB over 1 year ago will be allowed. Has known allergy to large molecule protein products or any compound of sintilimab. Has a known history of interstitial lung disease. Any other condition, including symptomatic heart failure, unstable angina, myocardial infarction, active infection requiring systemic therapy, mental illness or domestic/social factors, deemed by the investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interferes with the interpretation of the results.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adjuvant Sintilimab Plus Capecitabine<br>Lead-in Phase: Sintilimab (200mg, D1, D14 for 2 cycles); Adjuvant Phase: Sintilimab ( 200mg D1, every three weeks, a total of 24 weeks, 8 cycles) + Capecitabine ( 1000 mg/m2, BID, D1-14 every three weeks, a total of 24 weeks, 8 cycles). | Drug: Sintilimab<br>* Sintilimab is a humanized monoclonal antibody against Programmed death 1(PD-1).<br>* Other names: IBI308;Drug: Capecitabine<br>* An oral anticancer agent that can be converted into 5-Fu in vivo.<br>|
| Active Comparator: Adjuvant Capecitabine<br>Capecitabine 1000 mg/m2, BID, D1-14, every three weeks, a total of 24 weeks, 8 cycles. | Drug: Capecitabine<br>* An oral anticancer agent that can be converted into 5-Fu in vivo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progress-free survival (PFS) | Defined as the time from random assignment to documented local or regional relapse, distant metastasis, or death from any cause, whichever occurred first. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Defined as the time from random assignment to death from any cause or censored at the date of last follow-up | 2 years | 
| Locoregional Relapse-Free Survival (LRFS) | Defined as the time from random assignment to local or regional relapse, or death from any cause. | 2 years | 
| Distant Metastasis-Free Survival (DMFS) | Defined as the time from random assignment to distant metastasis, or death from any cause. | 2 years | 
| Incidence rate of adverse events (AEs) | Analysis of acute and late adverse events (AEs) are evaluated. Numbers of patients of treatment-related adverse events(acute toxicity) as assessed by CTCAE v5.0.Numbers of patients of late radiation toxicities were assessed using the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme. | 2 years |