QL1706 (PD-1/CTLA-4 Bi-specific Antibody) and Chemoradiotherapy in Locoregionally-advanced Nasopharyngeal Carcinoma.

Официальное название

QL1706 (Iparomlimab and Tuvonralimab Injection,PD-1/ CTLA-4 Bi-specific Antibody) Combined With Chemoradiotherapy Versus Chemoradiotherapy Alone in High-Risk Locoregionally Advanced Nasopharyngeal Carcinoma：A Randomized, Controlled, Multicenter Phase III Clinical Study.

Обзор

The trial aimed to compare QL1706 combined with induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) versus IC+CCRT alone in High-risk Locoregionally-Advanced Nasopharyngeal Carcinoma (LANPC).

Подробное описание

The trial plans to enroll patients with stage T4N1and T1-4N2-3 (AJCC 9th) 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 QL1706 in induction chemotherapy and adjuvant chemotherapy. All patients will receive intensity-modulated radiotherapy (IMRT). QL1706 will begin on day 1 of induction chemotherapy and continue every 3 weeks for 3 cycles in induction therapy and for 9 cycles in adjuvant therapy.

Вмешательства

• Препарат QL1706
  QL1706 5mg/kg will be given every 3 weeks for 3 cycles in induction chemotherapy and for 9 cycles in adjuvant chemotherapy, started on day 1 of induction chemotherapy and adjuvant chemotherapy, respectively.
• Препарат Gemcitabine
  Gemcitabine 1g/m2, d1 \& 8 of every cycle, every 3 weeks for 3 cycles before radiation.
• Препарат Cisplatin
  Induction cisplatin 80mg/m2, every 3 weeks for 3 cycles before radiation; Concurrent cisplatin 100mg/m2, every 3 weeks for 2 cycles during radiation
• Лучевая терапия Intensity-modulated radiotherapy
  Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy will be given in 33 fractions.

Первичные конечные точки

• Failure-free survival (FFS) in intention-to-treat population [Срок оценки: 3 years]
• Overall survival (OS) in intention-to-treat population [Срок оценки: 5 years]

Вторичные конечные точки (8)

• Failure-free survival (FFS) in per-protocol population [Срок оценки: 3 years]
• Overall survival (OS) in per-protocol population [Срок оценки: 3 years]
• Locoregional recurrence-free survival (LRRFS) [Срок оценки: 3 years]
• Distant metastasis-free survival (DMFS) [Срок оценки: 3 years]
• Adverse events (AEs) and serious adverse events (SAEs) [Срок оценки: 3 years]
• Quality of life (QoL) [Срок оценки: week 1, 20, 40, 64]
• Failure-free survival (FFS) within different subgroups [Срок оценки: 3 years]
• Tumor response [Срок оценки: Every 6 weeks（the time of completion of induction chemotherapy, radiotherapy, and adjuvnt immunotherapy; from the date of enrollment until the date of the last time that tumorimaging and assessment of disease has been done, assessed up to 74 weeks)]

Критерии участия

Критерии включения

• Age ≥18 and ≤65 years
• Patients with histologically confirmed non-keratinizing nasopharyngeal carcinoma according to WHO criteria.
• Tumor staged as T4N1 and T1-4N2-3 (AJCC 9th)

• Stage II: T1-3N2
• Stage III: T1-4N3, T4N1-2
• Eastern Cooperative Oncology Group performance score of 0-11.
• Adequate marrow function: white blood cell count > 4 × 10⁹/Lhemoglobin >90g/L and platelet count >100×10⁹/L
• Adequate hepatic and renal function：

• Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
• Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) ≤2.5×ULN
• Alkaline phosphatase ≤ 2.5 × ULN
• clearance rate ≥ 60 ml/min
• Other laboratory and clinical criteria

• Normal thyroid function, serum amylase and lipase, pituitary hormone levels, inflammatory markers, cardiac enzyme tests and electrocardiogram (ECG)
• For patients aged >50 years with a history of smoking, normal pulmonary function test (PFT) results are required
• For patients with abnormal ECG findings or a prior history of cardiovascular disease (not meeting any exclusion criteria listed in Item 8), additional assessments including myocardial function evaluation and cardiac ultrasound (echocardiography) must be performed, with results within normal limits
• Patients must be informed of the investigational nature of this study and give written informed consent, and be willing and able to comply with the study schedule, including follow-up visits, treatment procedures, laboratory testing, and other protocol-related requirements.
• Women of childbearing potential (WOCBP) must be willing to adhere to effective contraception during treatment and for 1 year after the last dose of study drug (e.g., condoms, physician-guided regular use of oral contraceptives).

Критерии исключения

• Positive for hepatitis B surface antigen (HBsAg) with hepatitis B virus DNA >1×103 copies/mL, positive for anti-hepatitis C virus (HCV) antibody , positive for anti-hepatitis C virus (HCV) antibody
• Positive for anti-HIV antibody or diagnosed with acquired immunodeficiency syndrome (AIDS).
• Active pulmonary tuberculosis: Patients with a history of active tuberculosis within the past year should be excluded regardless of treatment status. Patients with a history of active pulmonary tuberculosis more than one year prior should also be excluded, unless they received confirmed and regular anti-tuberculosis treatment.
• Active, known, or suspected autoimmune diseases, including but not limited to uveitis, colitis, hepatitis, hypophysitis, nephritis, vasculitis, systemic lupus erythematosus, hyperthyroidism, hypothyroidism, and asthma requiring bronchodilators. Type I diabetes, hypothyroidism treated with replacement therapy, and skin disease that doesn't require systemic treatment (e.g., vitiligo, psoriasis, or alopecia) are allowed.
• Thymic epithelial tumors (TETs), including thymoma, thymic carcinoma, and thymic neuroendocrine tumors (NETTs).
• History of interstitial lung disease or pneumonia requiring oral or intravenous corticosteroids within the past year; use of vancomycin within the past month.
• Ongoing chronic systemic corticosteroid therapy (equivalent to or greater than prednisone >10mg per day) or any other immunosuppressive therapy. Patients received inhale or topical corticosteroid are allowed.
• Uncontrolled cardiac conditions, such as:

• Heart failure with New York Heart Association (NYHA) classification ≥ Class II;
• Unstable angina;
• History of myocardial infarction within the past year;
• Supraventricular or ventricular arrhythmias requiring treatment or intervention
• Pregnant or breastfeeding women (pregnancy testing should be considered for women of childbearing potential with active sexual life)
• History or presence of other malignancies, except for adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, and papillary thyroid carcinoma.
• Known hypersensitivity to macromolecule protein products or any component of QL1706.
• Active infections requiring systemic treatment within 1 week prior to enrollment.
• Administration of live vaccines within 30 days prior to the first dose of epalurilimab-tovorolimab.
• History of organ transplantation or hematopoietic stem cell transplantation.
• Any other condition assessed by the investigator as potentially compromising patient safety or compliance, such as severe illnesses requiring urgent treatment (including psychiatric disorders), significantly abnormal laboratory values, or other psychological, familial, or social risk factors.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 19 центров

• Fujian Cancer Hospital — Фучжоу
• Dongguan People's Hospital — Дунгуань
• First People's Hospital of Foshan — Foshan
• Guangzhou Panyu Central Hospital — Гуанчжоу
• Sun Yat-Sen University Cancer Center — Гуанчжоу
• Zhongshan People's Hospital — Zhongshan
• Cancer Hospital of Guangxi Medical University — Nanning
• Cancer Hospital of Guizhou Medical University — Guiyang
• … и ещё 11 центров

Публикации

• Hsu C, Lee SH, Ejadi S, Even C, Cohen RB, Le Tourneau C, Mehnert JM, Algazi A, van Brummelen EMJ, Saraf S, Thanigaimani P, Cheng JD, Hansen AR. Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study. J Clin Oncol. 2017 Dec 20;35(36):4050-4056. doi: 10.1200/JCO.2017.73.3675. Epub 2017 Aug 24. PMID 28837405
• Zhao Y, Ma Y, Zang A, Cheng Y, Zhang Y, Wang X, Chen Z, Qu S, He J, Chen C, Jin C, Zhu D, Li Q, Liu X, Su W, Ba Y, Hao Y, Chen J, Zhang G, Qu S, Li Y, Feng W, Yang M, Liu B, Ouyang W, Liang J, Yu Z, Kang X, Xue S, Yang G, Yan W, Yang Y, Liu Z, Peng Y, Fanslow B, Huang X, Zhang L, Zhao H. First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with adv PMID 37158938
• Zhang Y, Chen L, Hu GQ, Zhang N, Zhu XD, Yang KY, Jin F, Shi M, Chen YP, Hu WH, Cheng ZB, Wang SY, Tian Y, Wang XC, Sun Y, Li JG, Li WF, Li YH, Tang LL, Mao YP, Zhou GQ, Sun R, Liu X, Guo R, Long GX, Liang SQ, Li L, Huang J, Long JH, Zang J, Liu QD, Zou L, Su QF, Zheng BM, Xiao Y, Guo Y, Han F, Mo HY, Lv JW, Du XJ, Xu C, Liu N, Li YQ, Chua MLK, Xie FY, Sun Y, Ma J. Gemcitabine and Cisplatin Induct PMID 31150573

Идентификаторы

NCT: NCT06749899 · 2024-FXY-409-FLK

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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