Combination of Toripalimab and Chemoradiotherapy in Esophageal Cancer

Study Overview
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Brief Summary
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Definitive chemoradiotherapy (CRT) is the standard treatment option for unresectable esophageal cancer (EC). However, as high as more than 40% of EC patients experienced locoregional recurrence after concurrent CRT. Immunotherapy targeting the PD-1/PD-L1 checkpoints has demonstrated promising activity in advanced EC. The aim of this study was to evaluate the efficacy and safety of the combination of toripalimab (an anti-PD-1 antibody) combined with definitive CRT in locally advanced esophageal squamous cell carcinoma (ESCC).

Official Title
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A Phase II Trial of Combination of Toripalimab and Definitive Chemoradiotherapy in Esophageal Squamous Cell Carcinoma

Conditions
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Unresectable Esophageal Cancer

Intervention / Treatment
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* Drug: Toripalimab
* Drug: Paclitaxel/Cisplatin
* Radiation: Intensity-modulated radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed squamous cell carcinoma of the esophagus; Absence of hematogenous metastasis disease, confirmed by endoscopic ultrasound (EUS) and PET-CT scan (according to UICC TNM version 8); Not suitable for surgery (either for medical reasons or patient's choice); Age at diagnosis 18 to 70 years; No prior cancer therapy; Estimated life expectancy >6 months; Eastern Cooperative Oncology Group performance status ≤ 2 No history of concomitant or previous malignancy; 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; Ability to understand the study and sign informed consent. Exclusion Criteria: Patients who have been treated previously with anti-tumor therapy (including chemotherapy, radiotherapy, surgery, immunotherapy, etc.); Patients with hematogenous metastasis disease at diagnosis; Known or suspected allergy or hypersensitivity to monoclonal antibodies, any ingredients of Toripalimab, and the chemotherapeutic drugs paclitaxel or cisplatin; Patients who have a preexisting or coexisting bleeding disorder; Female patients who are pregnant or lactating; Inability to provide informed consent due to psychological, familial, social and other factors; Presence of CTC grade ≥ 3 peripheral neuropathy; A history of malignancies other than esophageal cancer before enrollment, excluding non-melanoma skin cancer, in situ cervical cancer, or cured early prostate cancer A history of diabetes for more than 10 years and poorly controlled blood glucose levels; Patients who cannot tolerate chemoradiotherapy due to severe cardiac, lung, liver or kidney dysfunction, or hematopoietic disease or cachexia. 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; A history of interstitial lung disease or non-infectious pneumonia; 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; Presence of active hepatitis B (HBV DNA ≥ 2000 IU/mL or 104 copies/mL), hepatitis C hepatitis C antibody, and HCV-RNA levels higher than the lower limit of the assay).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PD-1 group<br>All patients will receive standard fractionation radiation therapy (RT) scheme: 50.4 Gy in 28 fractions over 5-6 weeks, concurrently with 5 cycles of paclitaxel/cisplatin (paclitaxel 50mg/m2 and cisplatin 25 mg/m2) on days 1, 8, 15, 22, 29 and 2 cycles of toripalimab 240 mg on days 1, 22 followed by a maintenance phase of toripalimab IV 240 mg every 3 weeks for up to 1 year. | Drug: Toripalimab<br>* Patients received toripalimab 240 mg on days 1 and 22 during radiotherapy followed by a maintenance phase of toripalimab IV 240 mg every 3 weeks for up to 1 year.<br>* Other names: JS-001;Drug: Paclitaxel/Cisplatin<br>* Patients received 5 cycles of paclitaxel/cisplatin (paclitaxel 50mg/m2 and cisplatin 25 mg/m2) on days 1, 8, 15, 22, 29 during radiotherapy.<br>* Other names: TP;Radiation: Intensity-modulated radiotherapy<br>* All patients received external-beam radiation using intensity-modulated radiotherapy. The prescribed dose is 50.4 Gy in 28 fractions over 5-6 weeks.<br>* Other names: IMRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical complete response rate | Tumor response was evaluated 3 months after the completion of chemoradiotherapy based on CT or PET-CT scans, endoscopy with biopsies. | 3 months after chemoradiotherapy (plus or minus 14 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year overall survival | The 2-year overall survival of the whole group | From date of randomization until the date of death from any cause or the date of last follow-up, whichever came first, assessed up to 24 months | 
| 2-year progression-free survival | The 2-year progression-free survival of the whole group | From date of randomization until the date of death from any cause or the date of first documented disease progression whichever came first, assessed up to 24 months | 
| Duration of response | Tumor response was evaluated every two months after chemoradiotherapy according to RECIST criteria | From date of first CR/PR to the date of first PD according to RECIST criteria, assessed up to 24 months | 
| Incidence of treatment-related adverse events as assessed by CTCAE v4.0 | Toxicity of treatment was evaluated according to CTCAE 4.0 | From the start of treatment to 2 year after the completion of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Esophageal squamous cell carcinoma, Definitive chemoradiotherapy, Toripalimab, Clinical complete response