Clinical trial NCT06187597: Consolidation of Toripalimab After Chemoradiotherapy in Elderly Esophageal Cancer (EC-CRT-007)
Official title: Efficacy and Safety of Toripalimab After Concurrent Chemoradiotherapy in Elderly Patients With Esophageal Squamous Cell Carcinoma: a Multicenter, Randomized, Phase II Trial (EC-CRT-007)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Locally Advanced Esophageal Squamous Cell Carcinoma
Keywords: Esophageal squamous cell carcinoma
Chemoradiotherapy
Immunotherapy
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
Collaborators: name: Nanfang Hospital, Southern Medical University
name: Zhujiang Hospital
name: Fifth Affiliated Hospital, Sun Yat-Sen University
name: Xiangya Hospital of Central South University
name: Wuhan University
First posted: 2024-01-02
Enrollment: 140
Sex: ALL
Minimum age (years): 70
Maximum age (years): 85
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Although definitive chemoradiotherapy (CRT) is the standard treatment option for unresectable locally advanced esophageal cancer, elderly patients tolerate intravenous concurrent CRT less well with age and comorbidities. Previous trials have demonstrated that CRT with oral S-1 was tolerable and provided significant survival benefits over radiotherapy alone in elderly patients with esophageal squamous cell carcinoma (ESCC). However, as high as 54% of patients with elderly ESCC experienced locoregional or distant recurrence after CRT. Therefore, a more effective regimen for older patients is needed. Immune checkpoint inhibitors targeting PD-1/PD-L1 have shown substantial clinical benefits in advanced esophageal cancer. Recently, the combination of immunotherapy with CRT has emerged as a promising strategy to improve clinical outcomes in locally advanced esophageal cancer. The aim of this study was to evaluate the efficacy and safety of toripalimab (an anti-PD-1 antibody) after concurrent CRT in elderly patients with locally advanced ESCC.

Detailed description: A total of 140 patients with elderly, unresectable, locally advanced ESCC will be stratified according to age (70-80 vs. ≥80) and TNM stage (I/II vs. III/IV) and randomly assigned (1:1) to receive toripalimab as consolidation therapy for up to 12 months (arm A) or not (arm B) after definitive radiotherapy with concurrent S-1.

Eligibility criteria: Inclusion Criteria:

1. Histologically confirmed squamous cell carcinoma of the esophagus;
2. Locally advanced, and absence of hematogenous metastasis disease according to UICC TNM version 8;
3. Not suitable for surgery (either for medical reasons or patient's choice);
4. Age at diagnosis 70 to 85 years;
5. No prior cancer therapy;
6. Estimated life expectancy \>6 months;
7. Eastern Cooperative Oncology Group performance status ≤ 2
8. No history of concomitant or previous malignancy;
9. The function of important organs meets the following requirements: a. white blood cell count (WBC) ≥4.0×109/L, absolute neutrophil count (ANC) ≥1.5×109/L; b. platelets ≥100×109/L; c. hemoglobin ≥9g/dL; d. serum albumin ≥2.8g/dL; e. total bilirubin ≤1.5×ULN, ALT, AST and/or AKP ≤2.5×ULN; f. serum creatinine ≤1.5×ULN or creatinine clearance rate \>60 mL/min;
10. Ability to understand the study and sign informed consent.

Exclusion Criteria:

1. Patients who have been treated previously with anti-tumor therapy (including chemotherapy, radiotherapy, surgery, immunotherapy, etc.);
2. Patients with hematogenous metastasis disease or esophageal fistula at diagnosis;
3. Known or suspected allergy or hypersensitivity to monoclonal antibodies, any ingredients of cadonilimab, and the chemotherapeutic drugs paclitaxel or cisplatin;
4. Patients who have a preexisting or coexisting bleeding disorder;
5. Inability to provide informed consent due to psychological, familial, social and other factors;
6. Presence of CTC grade ≥2 peripheral neuropathy;
7. A history of malignancies other than esophageal cancer before enrollment, excluding non-melanoma skin cancer, in situ cervical cancer, or cured early prostate cancer
8. A history of diabetes for more than 10 years and poorly controlled blood glucose levels;
9. Patients who cannot tolerate chemoradiotherapy due to severe cardiac, lung, liver or kidney dysfunction, or hematopoietic disease or cachexia.
10. Active autoimmune diseases, a history of autoimmune diseases (including but not limited to these diseases or syndromes, such as colitis, hepatitis, hyperthyroidism), a history of immunodeficiency (including a positive HIV test result), or other acquired or congenital immunodeficiency diseases, a history of organ transplantation or allogeneic bone marrow transplantation;
11. A history of interstitial lung disease or non-infectious pneumonia;
12. A history of active pulmonary tuberculosis infection within 1 year or a history of active pulmonary tuberculosis infection more than 1 year ago but without formal anti-tuberculosis treatment;
13. Presence of active hepatitis B (HBV DNA ≥ 2000 IU/mL or 104 copies/mL), hepatitis C (positive for hepatitis C antibody, and HCV-RNA levels higher than the lower limit of the assay).

Primary outcomes:
measure: Progression-free survival
timeFrame: From date of enrollment until the date of death from any cause or the date of first documented disease progression whichever came first, assessed up to 36 months.
Secondary outcomes:
measure: Overall survival
timeFrame: From date of enrollment until the date of death from any cause or the date of last follow-up, whichever came first, assessed up to 36 months.
measure: Clinical complete response
timeFrame: 13-16 weeks after the completion of radiotherapy
measure: Duration of response
timeFrame: From date of first CR/PR to the date of first PD according to RECIST criteria, assessed up to 36 months.
measure: Treatment-related adverse events
timeFrame: From date of enrollment to the date of last follow-up, assessed up to 36 months.
Other outcomes:
measure: Correlation between immune signature and overall survival
timeFrame: From date of enrollment to the date of last follow-up, assessed up to 36 months.
measure: Correlation between serum cytokines and overall survival and immune-related adverse events
timeFrame: From date of enrollment to the date of last follow-up, assessed up to 36 months.
Locations:
city: Guangzhou
country: China
facility: Mian Xi
state: Guangdong
Study officials:
affiliation: Sun Yat-sen University
name: Mian Xi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhu Y, Wen J, Li Q, Chen B, Zhao L, Liu S, Yang Y, Wang S, Lv Y, Li J, Zhang L, Hu Y, Liu M, Xi M. Toripalimab combined with definitive chemoradiotherapy in locally advanced oesophageal squamous cell carcinoma (EC-CRT-001): a single-arm, phase 2 trial. Lancet Oncol. 2023 Apr;24(4):371-382. doi: 10.1016/S1470-2045(23)00060-8.
citation: Ji Y, Du X, Zhu W, Yang Y, Ma J, Zhang L, Li J, Tao H, Xia J, Yang H, Huang J, Bao Y, Du D, Liu D, Wang X, Li C, Yang X, Zeng M, Liu Z, Zheng W, Pu J, Chen J, Hu W, Li P, Wang J, Xu Y, Zheng X, Chen J, Wang W, Tao G, Cai J, Zhao J, Zhu J, Jiang M, Yan Y, Xu G, Bu S, Song B, Xie K, Huang S, Zheng Y, Sheng L, Lai X, Chen Y, Cheng L, Hu X, Ji W, Fang M, Kong Y, Yu X, Li H, Li R, Shi L, Shen W, Zhu C, Lv J, Huang R, He H, Chen M. Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients With Esophageal Cancer: A Multicenter Randomized Phase 3 Clinical Trial. JAMA Oncol. 2021 Oct 1;7(10):1459-1466. doi: 10.1001/jamaoncol.2021.2705.
citation: Liu Y, Zheng Z, Li M, Zhang Y, Zhao F, Gong H, Lin H, Huang W, Chen X, Xu Z, Li X, Liu W, Cui Y, Zheng A, Li B. Comparison of concurrent chemoradiotherapy with radiotherapy alone for locally advanced esophageal squamous cell cancer in elderly patients: A randomized, multicenter, phase II clinical trial. Int J Cancer. 2022 Aug 15;151(4):607-615. doi: 10.1002/ijc.34030. Epub 2022 Apr 27.
citation: Wang X, Han W, Zhang W, Wang X, Ge X, Lin Y, Zhou H, Hu M, Wang W, Liu K, Lu J, Qie S, Zhang J, Deng W, Wang L, Han C, Li M, Zhang K, Li L, Wang Q, Shi H, Yu Z, Zhao Y, Sun X, Shi Y, Pang Q, Zhou Z, Liang J, Chen D, Feng Q, Bi N, Zhang T, Deng L, Wang W, Liu W, Wang J, Zhai Y, Wang J, Chen W, Chen J, Xiao Z; Jing-Jin-Ji Esophageal and Esophagogastric Cancer Radiotherapy Oncology Group (3JECROG). Effectiveness of S-1-Based Chemoradiotherapy in Patients 70 Years and Older With Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial. JAMA Netw Open. 2023 May 1;6(5):e2312625. doi: 10.1001/jamanetworkopen.2023.12625.