Adaptive Immunotherapy for Locoregional Nasopharyngeal Carcinoma: a Randomized, Controlled, Multicenter, Phase 3 Clinical Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 802
- 试验地点
- 1
- 主要终点
- Event-free survival
研究概览
简要总结
- To assess whether radiotherapy alone is non-inferior to concurrent chemoradiotherapy with respect to event-free survival and superior in reducing treatment-related nausea in low-risk locoregionally advanced nasopharyngeal carcinoma patients who achieve complete or partial response and undetectable serum EBV-DNA following induction chemoimmunotherapy.
- To evaluate whether adjuvant capecitabine and immunotherapy after concurrent chemoradiotherapy improves event-free survival compared to adjuvant immunotherapy in high-risk locoregionally advanced nasopharyngeal carcinoma patients with stable disease or detectable serum EBV-DNA after induction chemoimmunotherapy.
详细描述
Recent trials have demonstrated that for patients with locoregionally advanced nasopharyngeal carcinoma (NPC), the addition of immnotherapy to standard induction chemotherapy followed by concurrent chemoradiotherapy significantly improves event-free survival (EFS) (NCT03700476 and NCT03427827). However, current trials on immnotherapies lack specific biomarkers for risk stratification and adaptive treatment strategies.
Epstein-Barr virus (EBV) is closely associated with the development of NPC. Cell-free EBV-DNA released by NPC cells can be detected in peripheral blood and has been strongly correlated with patient prognosis. Prospective clinical trials (NCT03855020 and NCT04907370) have confirmed that patients with undetectable EBV-DNA after induction therapy exhibit significantly better EFS compared to those with detectable post-induction EBV-DNA.
Among low-risk patients with undetectable EBV-DNA after induction therapy, the 3-year EFS rate exceeds 90%. However, the combination of immunotherapy with concurrent cisplatin-based chemoradiotherapy also leads to significant treatment-related toxicities, with 74% of patients experiencing grade 3 or higher adverse events. Therefore, there is an urgent need to explore novel treatment strategies aimed at reducing toxicity in this patient population. Recent phase 3 multicenter randomized trials have demonstrated that de-intensification strategies omitting concurrent cisplatin chemotherapy significantly reduce treatment-related toxicities in both early-stage (NCT02633202) and locoregionally advanced NPC (NCT04907370), with reductions in grade 3 or higher adverse events by 29% and 11%, respectively.
Among high-risk patients with positive EBV-DNA after induction therapy, even with the combination of immuotherapy, the 3-year EFS remains suboptimal, ranging from 65% to 80%. There is a critical need for treatment intensification strategies to improve outcomes in this group. A recently completed multicenter, randomized, phase 3 trial (NCT02958111) demonstrated that adjuvant metronomic capecitabine (650 mg/m² twice daily) for one year following standard induction chemotherapy and concurrent chemoradiotherapy significantly improved 3-year EFS from 75.7% to 85.3% in high-risk locoregionally advanced NPC patients, with a manageable toxicity profile.
Therefore, the investigators propose the following scientific hypothesis: in low-risk patients who achieve complete or partial response and undetectable serum EBV-DNA following induction chemoimmunotherapy, radiotherapy alone can reduce the incidence of treatment-related adverse effects, without reducing survival; in high-risk patients with stable disease or detectable serum EBV-DNA, adjuvant capecitabine and immunotherapy can improve survival.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •18-65 years;
- •Newly diagnosed, pathologically confirmed non-keratinizing carcinoma (according to WHO criteria);
- •Locoregionally advanced nasopharyngeal carcinoma (Stage II-III) as defined by the 9th edition of the American Joint Committee on Cancer (AJCC) staging system;
- •ECOG performance status: 0-1;
- •Adequate bone marrow function: white blood cell count > 4 × 10⁹/L, hemoglobin > 90 g/L, platelet count > 100 × 10⁹/L;
- •Normal renal and hepatic function: total bilirubin ≤ 1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 × ULN; alkaline phosphatase ≤ 2.5 × ULN; creatinine clearance ≥ 60 mL/min;
- •Normal thyroid function, amylase, lipase, pituitary function;
- •Completion of 3 cycles of GP regimen induction chemotherapy combined with PD-1 inhibitor immunotherapy;
- •Patients must provide signed informed consent and be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures;
- •Female participants of childbearing potential must agree to use reliable contraceptive methods (e.g., condoms, regular use of oral contraceptives as prescribed) from screening until one year after treatment.
排除标准
- •T3N0-1, according to the American Joint Committee on Cancer (AJCC) Staging System, 9th Edition;
- •Disease progression after induction therapy;
- •Hepatitis B surface antigen (HBsAg) positive with HBV DNA >1×10³ copies/mL, or anti-hepatitis C virus (HCV) antibody positive;
- •Anti-HIV antibody positive or diagnosed with acquired immunodeficiency syndrome (AIDS);
- •Active tuberculosis;
- •Active, known, or suspected autoimmune disease. Exceptions include type 1 diabetes, hypothyroidism requiring hormone replacement therapy, and skin disorders not requiring systemic treatment (e.g., vitiligo, psoriasis, or alopecia);
- •History of interstitial lung disease or pneumonia requiring oral or intravenous steroid treatment within the past year;
- •Chronic systemic glucocorticoid therapy or any other form of immunosuppressive therapy. Subjects using inhaled or topical corticosteroids are eligible;
- •Uncontrolled cardiac disease;
- •Pregnant or lactating women;
- •History or current diagnosis of another malignancy, except for adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, or papillary thyroid carcinoma;
- •Known allergy to macromolecular protein preparations or any component of toripalimab;
- •Active infection requiring systemic treatment within one week prior to enrollment;
- •Administration of a live vaccine within 30 days before the first dose of toripalimab;
- •History of organ transplantation;
- •Contraindications to MRI examination, which would prevent the completion of required imaging;
- •Any other condition deemed by the investigators to potentially compromise patient safety or compliance.
研究组 & 干预措施
High risk arm 1
Adjuvant capecitabine and immunotherapy after concurrent chemoradiotherapy
干预措施: Concurrent chemoradiotherapy (cCRT) (Drug)
High risk arm 1
Adjuvant capecitabine and immunotherapy after concurrent chemoradiotherapy
干预措施: Capecitabine (Drug)
Low risk arm 1
Radiotherapy alone
干预措施: Radical radiotherapy of nasopharynx and neck (Radiation)
Low risk arm 1
Radiotherapy alone
干预措施: Toripalimab (Drug)
Low risk arm 2
Concurrent chemoradiotherapy
干预措施: Radical radiotherapy of nasopharynx and neck (Radiation)
Low risk arm 2
Concurrent chemoradiotherapy
干预措施: Concurrent chemoradiotherapy (cCRT) (Drug)
Low risk arm 2
Concurrent chemoradiotherapy
干预措施: Toripalimab (Drug)
High risk arm 1
Adjuvant capecitabine and immunotherapy after concurrent chemoradiotherapy
干预措施: Radical radiotherapy of nasopharynx and neck (Radiation)
High risk arm 1
Adjuvant capecitabine and immunotherapy after concurrent chemoradiotherapy
干预措施: Toripalimab (Drug)
High risk arm 2
Adjuvant immunotherapy after concurrent chemoradiotherapy
干预措施: Radical radiotherapy of nasopharynx and neck (Radiation)
High risk arm 2
Adjuvant immunotherapy after concurrent chemoradiotherapy
干预措施: Concurrent chemoradiotherapy (cCRT) (Drug)
High risk arm 2
Adjuvant immunotherapy after concurrent chemoradiotherapy
干预措施: Toripalimab (Drug)
结局指标
主要结局
Event-free survival
时间窗: 3 year
The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population.
Incidence rates of vomiting as assessed by CTCAE v5.0
时间窗: 3 year
In the low-risk arm, the primary outcome included the incidence rates of vomiting (evaluated according to the Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0).
次要结局
- Overall survival(3 year)
- Locoregional relapse-free survival(3 year)
- Distant metastasis-free survival(3 year)
- Number of participants with treatment-related adverse events as assessed by CTCAE v5.0(3 year)
- Number of participants with treatment-related adverse events as assessed by RTOG/EORTC System(3 year)
- Patient's quality-of-life as assessed by EORTC QLQ-C30(3 year)
- Patient's quality-of-life as assessed by QLQ-H&N35 v1.0(3 year)
- Patient-reported tolerability as assessed by PRO-CTCAE v1.0(3 year)
研究者
Ling-Long Tang
Prof.
Sun Yat-sen University