Cadonilimab (PD-1/CTLA-4 Bispecific Blockade) and Chemoradiotherapy in Nasopharyngeal Carcinoma (GEMSTONE)

The trial plans to enroll patients with non-metastatic stage III-IVA (AJCC 8th, T4N1 or T1-4N2-3) locoregionally-advanced nasopharyngeal carcinoma (LANPC). Patients were randomly assigned in a 1:1 ratio to receive either gemcitabine-cisplatin induction chemotherapy and concurrent chemoradiotherapy (standard-therapy group) or cadonilimab combined with standard therapy (cadonilimab group). Cadonilimab was administered at a dosage of 10 mg per square meter intravenously once every 3 weeks for up to 17 cycles (3 induction cycles and 14 adjuvant cycles).

• Cadonilimab (Drug), also known as PD-1/CTLA-4 bi-specific antibody: Cadonilimab 10mg/kg will be given every 3 weeks for 3 cycles in induction chemotherapy and for 14 cycles in adjuvant chemotherapy, started on day 1 of induction chemotherapy and adjuvant chemotherapy, respectively.
• Gemcitabine (Drug), also known as GEM: Gemcitabine 1g/m2, d1 \& 8 of every cycle, every 3 weeks for 3 cycles before radiation.
• Cisplatin (Drug), also known as DDP: Induction cisplatin 80mg/m2, every 3 weeks for 3 cycles before radiation; Concurrent cisplatin 100mg/m2, every 3 weeks for 2 cycles during radiation
• Intensity-modulated radiotherapy (Radiation), also known as IMRT: Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy will be given in 33 fractions.

Primary outcomes

• Failure-free survival (FFS) in intention-to-treat population [3 years]: multiple endpoint 1: calculated from randomization to the date of locoregional recurrence, distant metastasis, or death from any cause, whichever occurred first.
• Overall survival (OS) in intention-to-treat population [3 years]: multiple endpoint 2: calculated from randomization to the date of death from any cause.

Secondary outcomes

• Failure-free survival (FFS) in per-protocol population [3 years]: calculated from randomization to the date of locoregional recurrence, distant metastasis, or death from any cause, whichever occurred first.
• Overall survival (OS) in per-protocol population [3 years]: calculated from randomization to the date of death from any cause.
• Locoregional recurrence-free survival (LRRFS) [3 years]: calculated from randomization to the date of locoregional persistence or 1st locoregional recurrence.
• Distant metastasis-free survival (DMFS) [3 years]: calculated from randomization to the date of first distant metastasis.
• Adverse events (AEs) and serious adverse events (SAEs) [3 years]: Graded according to CTCAE V5.0.
• Quality of life (QoL) [week 1, 20, 40, 64]: The change of QoL from randomization to the start of radiotherapy, the end of radiotherapy, 13-16 weeks after radiotherapy, 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.
• Failure-free survival (FFS) within different subgroups [3 years]: analyses for FFS will be performed within the following subgroups: Epstein-Barr virus (EBV) DNA (≤4000copies/ml vs. >4000copies/ml), different PD-L1 expression levels, age, gender, performance status, T category, N category, and stage (III vs. IVA).
• Tumor response [Through study completion, an average of 1.2 year]: Evaluation of tumor response as CR, PR, SD, PD, NA by clinicians

Other outcomes

• Correlation between pre-treatment PD-L1 expression level and FFS [3 years]: Pre-treatment PD-L1 expression level of tumor cell is evaluated centrally by means of immunohistochemical testing.
• Evaluate failure-free survival in the subgroup of plasma Epstein-Barr virus DNA level [3 years]: Subgroup analysis
• Evaluate failure-free survival in the subgroup of clinical stage [3 years]: Subgroup analysis

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

1. Patients with histologically confirmed nasopharyngeal carcinoma.
2. Tumor staged as III-IVA (AJCC 8th, except T3N0-1 or T4N0).
3. Eastern Cooperative Oncology Group performance status ≤1.
4. Adequate marrow function: neutrocyte count≥1.5×10e9/L, hemoglobin ≥90g/L and platelet count ≥100×10e9/L.
5. Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) ≤2.5×upper limit of normal (ULN), and bilirubin ≤ 1.5×ULN.
6. Adequate renal function: creatinine clearance rate ≥ 60 ml/min (Cockcroft-Gault formula).
7. Patients must be informed of the investigational nature of this study and give written informed consent.
8. 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:

1. Age > 65 or < 18.
2. Hepatitis B surface antigen (HBsAg) positive and hepatitis B virus DNA >1×10e3 copies/ml or 200IU/ml
3. Hepatitis C virus (HCV) antibody positive
4. 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).
5. 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.
6. 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.
7. Has a known history of interstitial lung disease.
8. Has received a live vaccine within 30 days before informed consent or will receive a live vaccine in the near future.
9. Is pregnant or breastfeeding.
10. Prior malignancy within 5 years, except in situ cancer, adequately treated non-melanoma skin cancer, and papillary thyroid carcinoma.
11. Has known allergy to large molecule protein products or any compound of cadonilimab.
12. Has a known history of human immunodeficiency virus (HIV) infection.
13. 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.

• Results publication: 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. PMID 31150573
• Results publication: Keam SJ. Cadonilimab: First Approval. Drugs. 2022 Aug;82(12):1333-1339. doi: 10.1007/s40265-022-01761-9. PMID 35986837
• Results publication: 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
• Results publication: Ma BBY, Lim WT, Goh BC, Hui EP, Lo KW, Pettinger A, Foster NR, Riess JW, Agulnik M, Chang AYC, Chopra A, Kish JA, Chung CH, Adkins DR, Cullen KJ, Gitlitz BJ, Lim DW, To KF, Chan KCA, Lo YMD, King AD, Erlichman C, Yin J, Costello BA, Chan ATC. Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). J Clin Oncol. 2018 May 10;36(14):1412-1418. doi: 10.1200/JCO.2017.77.0388. Epub 2018 Mar 27. PMID 29584545

• Jun Ma, M.D., Principal investigator, Sun Yat-sen University