Clinical trial NCT06749899: QL1706 (PD-1/CTLA-4 Bi-specific Antibody) and Chemoradiotherapy in Locoregionally-advanced Nasopharyngeal Carcinoma.
Official title: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Nasopharyngeal Cancinoma (NPC)
Nasopharyngeal Cancer
Keywords: Immunotherapy
PD-1/CTLA-4 Bi-specific Antibody
Chemoradiotherapy
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
Collaborators: name: Qilu Pharmaceutical Co., Ltd.
First posted: 2024-12-27
Enrollment: 580
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria

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

   * Stage II: T1-3N2
   * Stage III: T1-4N3, T4N1-2
4. Eastern Cooperative Oncology Group performance score of 0-11.
5. Adequate marrow function: white blood cell count \> 4 × 10⁹/Lhemoglobin \>90g/L and platelet count \>100×10⁹/L
6. 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
7. 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
8. 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.
9. 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).

Exclusion Criteria

1. 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
2. Positive for anti-HIV antibody or diagnosed with acquired immunodeficiency syndrome (AIDS).
3. 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.
4. 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.
5. Thymic epithelial tumors (TETs), including thymoma, thymic carcinoma, and thymic neuroendocrine tumors (NETTs).
6. History of interstitial lung disease or pneumonia requiring oral or intravenous corticosteroids within the past year; use of vancomycin within the past month.
7. 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.
8. 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
9. Pregnant or breastfeeding women (pregnancy testing should be considered for women of childbearing potential with active sexual life)
10. History or presence of other malignancies, except for adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, and papillary thyroid carcinoma.
11. Known hypersensitivity to macromolecule protein products or any component of QL1706.
12. Active infections requiring systemic treatment within 1 week prior to enrollment.
13. Administration of live vaccines within 30 days prior to the first dose of epalurilimab-tovorolimab.
14. History of organ transplantation or hematopoietic stem cell transplantation.
15. 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.

Primary outcomes:
measure: Failure-free survival (FFS) in intention-to-treat population
timeFrame: 3 years
measure: Overall survival (OS) in intention-to-treat population
timeFrame: 5 years
Secondary outcomes:
measure: Failure-free survival (FFS) in per-protocol population
timeFrame: 3 years
measure: Overall survival (OS) in per-protocol population
timeFrame: 3 years
measure: Locoregional recurrence-free survival (LRRFS)
timeFrame: 3 years
measure: Distant metastasis-free survival (DMFS)
timeFrame: 3 years
measure: Adverse events (AEs) and serious adverse events (SAEs)
timeFrame: 3 years
measure: Quality of life (QoL)
timeFrame: week 1, 20, 40, 64
measure: Failure-free survival (FFS) within different subgroups
timeFrame: 3 years
measure: Tumor response
timeFrame: 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)
Other outcomes:
measure: Correlation between pre-treatment PD-L1 expression level and FFS
timeFrame: 3 years
measure: Evaluate failure-free survival in the subgroup of plasma Epstein-Barr virus DNA level
timeFrame: 3 years
measure: Evaluate failure-free survival in the subgroup of clinical stage
timeFrame: 3 years
Locations:
city: Fuzhou,
country: China
facility: Fujian Cancer Hospital
state: Fujian
city: Dongguan
country: China
facility: Dongguan People's Hospital
state: Guangdong
city: FoShan
country: China
facility: First People's Hospital of Foshan
state: Guangdong
city: Guangzhou
country: China
facility: Guangzhou Panyu Central Hospital
state: Guangdong
city: GuangZhou
country: China
facility: Sun Yat-Sen University Cancer Center
state: Guangdong
city: Zhongshan
country: China
facility: Zhongshan People's Hospital
state: Guangdong
city: Nanning
country: China
facility: Cancer Hospital of Guangxi Medical University
state: Guangxi
city: Guiyang
country: China
facility: Cancer Hospital of Guizhou Medical University
state: Guizhou
city: WuHan
country: China
facility: Hubei Province Cancer Hosiptal
state: Hubei
city: Wuhan
country: China
facility: Renmin Hospital of Wuhan University
state: Hubei
city: WuHan
country: China
facility: Tongji Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology
state: Hubei
city: Wuhan
country: China
facility: Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology
state: Hubei
city: ChangSha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: ChangSha
country: China
facility: Xiangya Hospital of Central South University
state: Hunan
city: Nanjing
country: China
facility: Jiangsu Cancer Hospital
state: Jiangsu
city: Shanghai
country: China
facility: The Eye and ENT Hospital of Fudan University
state: Shanghai
city: Chengdu
country: China
facility: Sichuan Cancer Hospital
state: Sichuan
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute ＆ Hospital
state: Tianjin
city: Fujian
country: China
facility: The First Affiliated Hospital of Xiamen University
state: Xiamen
Study officials:
affiliation: Sun Yat-sen University
name: Jun Ma, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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 advanced solid tumors. J Hematol Oncol. 2023 May 8;16(1):50. doi: 10.1186/s13045-023-01445-1.
citation: 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 Induction Chemotherapy in Nasopharyngeal Carcinoma. N Engl J Med. 2019 Sep 19;381(12):1124-1135. doi: 10.1056/NEJMoa1905287. Epub 2019 May 31.