Concurrent and Adjuvant PD-1 Blockade Combined With Induction Chemotherapy Plus Radiotherapy in Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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This is a phase 2, single-arm, multicenter clinical trial, with the purpose to evaluate the therapeutic efficacy and safety of PD-1 Blockade combined with induction chemotherapy and radiotherapy alone in high-risk locoregionally advanced nasopharyngeal carcinoma.

Detailed Description
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This phase 2, single-arm, multicenter clinical trial plans to enroll 146 patients with newly-diagnosed, pathologically-proven, untreated locoregionally advanced nasopharyngeal carcinoma (LANPC) at high-risk of distant metastasis (T4N1 and T1-4N2-3, according to American Joint Committee on Cancer [AJCC]/Union for International Cancer Control [UICC] 8th edition clinical staging system). Patients will receive 3 cycles of induction chemotherapy (IC; gemcitabine-cisplatin regimen) followed by intensity-modulated radiotherapy (IMRT) alone. Nivolumab injection OPDIVO® will start on day 1 of the first cycle IC and continue every 3 weeks for 6 cycles till the end of IMRT, involving the whole-course of IC + IMRT alone. The first and last 3 cycles of nivolumab are administrated concurrently with IC and IMRT, respectively. After 4 weeks of the completion of IMRT, adjuvant nivolumab will begin every 4 weeks for 6 cycles.

Official Title
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Whole-course Concurrent and Adjuvant Nivolumab Combined With Induction Chemotherapy Followed by Radiotherapy Alone in Locoregionally Advanced Nasopharyngeal Carcinoma: A Phase 2, Multi-center, Single-arm Clinical Trial

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Drug: PD-1 blocking antibody
* Drug: Gemcitabine
* Drug: Cisplatin
* Radiation: Intensity-modulated radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18 to 65; Pathological type: non-keratinizing carcinoma (World Health Organization criteria); Diagnosed with LANPC (T4N1, T1-4N2-3) according to the 8th edition clinical staging system of the American Joint Committee on Cancer [AJCC]/Union for International Cancer Control [UICC]; ECOG performance score: 0 to 1; Normal bone marrow function: white blood cell count > 4×109/L, hemoglobin > 90g/L, platelet count > 100×109/L; Normal values of thyroid function, amylase and lipase examination, pituitary function, inflammation and infection indicators, myocardial enzymes, and ECG results. For patients older than 50 years with a smoking history, normal lung function are required. Patients with abnormal ECG and/or a history of vascular disease (but not meeting the exclusion criteria listed in the exclusion criteria 7) need further testing and require normal results of myocardial function and color Doppler ultrasound. Normal liver and kidney function: total bilirubin ≤ 1.5 × upper limit of normal (ULN); alanine transaminase and aspartate transaminase ≤ 2.5 × ULN; alkaline phosphatase ≤ 2.5 × ULN; creatinine clearance rate ≥ 60 ml/min; Patients must sign informed consent and be willing and able to comply with the requirements of visits, treatment, laboratory tests and other research requirements stipulated in the research schedule; Subjects with pregnancy ability must agree to use reliable contraceptive measures from screening to 1 year after treatment. Exclusion Criteria: Hepatitis B virus surface antigen (HBsAg) positive and HBV DNA > 1×10E3 copies/ml; anti-hepatitis C virus positive; Anti-human immunodeficiency virus (HIV) positive or diagnosed with acquired immune deficiency syndrome (AIDS); Active tuberculosis: active tuberculosis in the past 1 year should be excluded regardless with treatment; history of active tuberculosis over 1 year should be excluded except that previous regulatory anti-tuberculosis treatment is proved; 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, skin disorders requiring no systemic treatment (such as vitiligo, psoriasis or alopecia); Previous interstitial lung disease or pneumonia requiring oral or intravenous steroid therapy; Chronic treatment with systemic glucocorticoid (dose equivalent to or over 10 mg prednisone per day) or any other form of immunosuppressive therapy. Subjects who used inhaled or topical corticosteroids were eligible; Uncontrolled heart disease, for example: 1) heart failure (NYHA level ≥ 2); 2) unstable angina; 3) myocardial infarction in past 1 year; 4) supraventricular or ventricular arrhythmia requiring treatment or intervention; Pregnant or lactating women (pregnancy test should be considered for women with sexual life and fertility); Previous or concurrent with other malignant tumors, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ and thyroid papillary cancer; Allergy to macromolecular protein preparations, or any component of nivolumab; Active infection requiring systemic treatment; Receiving live vaccine within 30 days of the initial nivolumab; History of organ transplantation; History of psychotropic disease, alcoholism or drug abuse; other situation assessed by the investigators that may compromise the safety or compliance of patients, such as serious disease requiring timely treatment (including mental illness), severe laboratory abnormalities, or family-social risk factors.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PD-1 blocking antibody combined with IC+IMRT<br>All participants will receive induction chemotherapy (IC; every 3 weeks × 3 cycles; gemcitabine 1000 mg/m2 day 1, 8 + cisplatin 80 mg/m2 day 1) followed by intensity-modulated radiotherapy (IMRT; 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day) alone. PD-1 blocking antibody (360 mg per cycle) will start on day 1 of the first cycle IC and continue every 3 weeks for 6 cycles till the end of IMRT, involving the whole-course of IC + IMRT alone. The first and last 3 cycles of PD-1 blocking antibody are administrated concurrently with IC and IMRT, respectively. After 4 weeks of the completion of IMRT, adjuvant PD-1 blocking antibody (480 mg per cycle) will begin every 4 weeks for 6 cycles. | Drug: PD-1 blocking antibody<br>* Whole-course concurrent PD-1 blocking antibody: every 3 weeks × 6 cycles; 360 mg, day 1; start on day 1 of the first cycle IC and continue every 3 weeks for 6 cycles till the end of IMRT, involving the whole-course of IC + IMRT alone. Adjuvant PD-1 blocking antibody: every 4 weeks × 6 cycles; 480 mg, day 1<br>* Other names: PD-1 blockade;Drug: Gemcitabine<br>* Gemcitabine as induction chemotherapy, 1000 mg/m2 day 1, 8 per cycle, every 3 weeks for 3 cycles<br>* Other names: GEM;Drug: Cisplatin<br>* Cisplatin as induction chemotherapy, 80 mg/m2 day 1 per cycle, every 3 weeks for 3 cycles<br>* Other names: DDP;Radiation: Intensity-modulated radiotherapy<br>* Definitive IMRT of 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day<br>* Other names: IMRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure-free survival (FFS) | Failure-free survival is measured from day of diagnosis until treatment failure, death from any cause, or last follow-up visit, whichever occurred first | 3-year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Overall survival is measured from day of diagnosis until death due to any cause or the latest known date alive | 3-year | 
| Locoregional failure-free survival (LRFFS) | Locoregional failure-free survival is measured from day of diagnosis until local or regional recurrence | 3-year | 
| Distant failure-free survival (DFFS) | Distant failure-free survival is measured from day of diagnosis until distant metastasis | 3-year | 
| Incidence rate of investigator-reported adverse events (AEs) | Analysis of investigator-reported adverse events (AEs) are based on treatment-related AEs (trAEs) and immune-related AEs (irAEs), and all-grade AEs and grade 3-4 AEs. AEs are evaluated by investigators according to the Common Terminology Criteria for Adverse Events, version 5.0 | 3-year | 
| Incidence rate of patient-reported adverse events (AEs) | Analysis of patient-reported adverse events (AEs) are based on treatment-related AEs (trAEs) and immune-related AEs (irAEs), and all-grade AEs and grade 3-4 AEs. AEs are evaluated by patients themselves | 3-year | 
| Quality of life (QoL): questionnaire | Changes in QoL of participants from initial treatment to 6 months after the completion of 6 cycles adjuvant PD-1 blocking antibody. QoL is evaluated with the use of (1) the head-and-neck-specific module (H&N35) of the Quality of Life Questionnaire-Core 30 module (QLQ-C30), which is established by European Organization for Research and Treatment of Cancer (EORTC) and (2) the general and head-and-neck-specific module of the evaluation tool developed by the Functional Assessment of Cancer Therapy (FACT). Scores for the module range of H&N35 QLQ-C30 from 0 to 100, with higher scores indicating better functioning or well-being or higher symptom burden (scales measuring symptom burden were reverse-scored to facilitate presentation) | week 1, 20, 40, 64 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD-1 blockade, immune checkpoint inhibitor, induction chemotherapy, radiotherapy