Sintilimab (PD-1 Antibody) and Chemoradiotherapy in Locoregionally-advanced Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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The CONTINUUM trial plans to enroll patients with stage III-IVA (AJCC 8th, except T3N0-1 or T4N0) locoregionally-advanced nasopharyngeal carcinoma (LANPC). Patients will be randomized in a 1:1 ratio to receive 3 cycles of induction chemotherapy with gemcitabine and cisplatin and concurrent cisplatin-radiation or the same regimen plus Sintilimab. All patients will receive intensity-modulated radiotherapy (IMRT). Sintilimab will begin on day 1 of induction chemotherapy and continue every 3 weeks for 12 cycles.

Official Title
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Sintilimab (PD-1 Antibody) and Chemoradiotherapy in Locoregionally-advanced Nasopharyngeal Carcinoma: a Randomized, Multicenter, Phase 3 Trial

Conditions
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Nasopharyngeal Neoplasms

Intervention / Treatment
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* Drug: Sintilimab
* Drug: Gemcitabine
* Drug: Cisplatin
* Radiation: intensity-modulated radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically confirmed nasopharyngeal carcinoma. Tumor staged as III-IVA (AJCC 8th, except T3N0-1 or T4N0). Eastern Cooperative Oncology Group performance status ≤1. 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: Age > 65 or < 18. 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 a known history of interstitial lung disease. 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. Prior malignancy within 5 years, except in situ cancer, adequately treated non-melanoma skin cancer, and papillary thyroid carcinoma. Has known allergy to large molecule protein products or any compound of sintilimab. Has a known history of human immunodeficiency virus (HIV) infection. 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: 65 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: Sintilimab arm<br>Patients will receive induction chemotherapy with gemcitabine (1g/m2, d1 & 8 of every cycle) and cisplatin (80mg/m2, d1 of every cycle), every 3 weeks for 3 cycles before radiation. Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy in 33 fractions will be given. Concurrent cisplatin of 100mg/m2 will be administered every 3 weeks for 2 cycles during IMRT. Sintilimab 200mg will be given every 3 weeks for 12 cycles, started on day 1 of induction chemotherapy. | Drug: Sintilimab<br>* Sintilimab 200mg will be given every 3 weeks for 12 cycles, started on day 1 of induction chemotherapy.<br>* Other names: PD-1 antibody;Drug: Gemcitabine<br>* Gemcitabine 1g/m2, d1 & 8 of every cycle, every 3 weeks for 3 cycles before radiation.<br>Drug: Cisplatin<br>* Induction cisplatin 80mg/m2, every 3 weeks for 3 cycles before radiation; Concurrent cisplatin 100mg/m2, every 3 weeks for 2 cycles during radiation<br>* Other names: DDP;Radiation: intensity-modulated radiotherapy<br>* Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy will be given in 33 fractions.<br>* Other names: IMRT;|
| Active Comparator: Chemoradiation arm<br>Patients will receive induction chemotherapy with gemcitabine (1g/m2, d1 & 8 of every cycle) and cisplatin (80mg/m2, d1 of every cycle), every 3 weeks for 3 cycles before radiation. Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy in 33 fractions will be given. Concurrent cisplatin of 100mg/m2 will be administered every 3 weeks for 2 cycles during IMRT. | Drug: Gemcitabine<br>* Gemcitabine 1g/m2, d1 & 8 of every cycle, every 3 weeks for 3 cycles before radiation.<br>Drug: Cisplatin<br>* Induction cisplatin 80mg/m2, every 3 weeks for 3 cycles before radiation; Concurrent cisplatin 100mg/m2, every 3 weeks for 2 cycles during radiation<br>* Other names: DDP;Radiation: intensity-modulated radiotherapy<br>* Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy will be given in 33 fractions.<br>* Other names: IMRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | calculated from randomization to the date of locoregional recurrence, distant metastasis, or death from any cause, whichever occurred first. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | calculated from randomization to the date of death from any cause. | 3 years | 
| Distant metastasis-free survival (DMFS) | calculated from randomization to the date of first distant metastasis, or death from any cause, whichever occurred first. | 3 years | 
| Locoregional recurrence-free survival (LRFS) | calculated from randomization to the date of locoregional persistence, 1st locoregional recurrence, or death from any cause, whichever occurred first. | 3 years | 
| Adverse events (AEs) and serious adverse events (SAEs) | Graded according to CTCAE V5.0. | 3 years | 
| Quality of life (QoL) | The change of QoL from randomization to the start of radiotherapy, the end of radiotherapy, 34 weeks (at the end of sintilimab treatment in the sintilimab arm and the corresponding timepoint in the chemoradiation arm), 2 years and 3 years after randomization. The EORTC QoL questionnaire-C30 (EORTC QLQ-C30）version 3.0 will be used. This questionnaire comprises 30 questions, 24 of which are aggregated into nine multi-question scales, that is, five functioning scales (e.g., physical), three symptom scales (e.g., fatigue) and one global health status scale. The remaining six single-question (e.g., dyspnoea) scales assess symptoms. These 15 scales will be scored according to the official Scoring Manual. | 3 years | 
| Event-free survival (EFS) within different subgroups | analyses for EFS will be performed within the following subgroups: Epstein-Barr virus (EBV) DNA (<4000copies/ml vs. ≥4000copies/ml), different PD-L1 expression levels (<1% vs. ≥1%), tertiary lymphoid structure (+ vs. -), age, gender, performance status, T category, N category, and stage (III vs. IVA). | 3 years |