Combination of Toripalimab and Neoadjuvant Chemoradiotherapy in Esophageal Cancer

Study Overview
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Brief Summary
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Neoadjuvant chemoradiotherapy (CRT) followed by surgery has become the standard treatment option for locally advanced esophageal cancer (EC). However, only 20% to 40% of EC patients can achieve pathologic complete response (pCR) after neoadjuvant CRT with favorable prognosis. 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 neoadjuvant CRT in locally advanced esophageal squamous cell carcinoma (ESCC).

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

Conditions
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Esophageal Squamous Cell Carcinoma by AJCC V8 Stage, Resectable Esophageal Cancer

Intervention / Treatment
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* Drug: Toripalimab
* Drug: Paclitaxel/cisplatin
* Radiation: Intensity-modulated radiotherapy
* Procedure: Esophagectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A histopathological diagnosis of resectable thoracic esophageal squamous cell carcinoma with a pre-treatment clinical stage of T1-4aN1-3M0 or T3-4aN0M0 according to the 8th edition of the UICC staging system; Patients who are anti-tumor treatment-naive; Estimated life expectancy >6 months Aged 18 to 70 years old of either gender 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; PS score of 0-1; 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.); 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; Other uncontrollable inoperable patients; 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 or surgery 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 (positive for 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: Toripalimab group<br>All patients will receive standard fractionation radiation therapy (RT) scheme: 44Gy in 20 fractions over 4 weeks, concurrently with 4 cycles of paclitaxel/cisplatin (paclitaxel 50mg/m2 and cisplatin 25 mg/m2) on days 1, 8, 15, 22 and 2 cycles of toripalimab 240 mg on days 1, 22. Esophagectomy is performed 6-8 weeks after CRT completion. | Drug: Toripalimab<br>* Patients received toripalimab 240 mg IVDRIP on days 1 and 22 during neoadjuvant radiotherapy.<br>* Other names: JS-001;Drug: Paclitaxel/cisplatin<br>* Patients received 4 cycles of paclitaxel/cisplatin (paclitaxel 50mg/m2 and cisplatin 25 mg/m2) on days 1, 8, 15, 22 during neoadjuvant radiotherapy.<br>* Other names: TP;Radiation: Intensity-modulated radiotherapy<br>* All patients received external-beam radiation using intensity-modulated radiotherapy. The prescribed dose is 44 Gy in 20 fractions over 4 weeks.<br>* Other names: IMRT;Procedure: Esophagectomy<br>* A transthoracic (Ivor-Lewis) esophagectomy is performed 6-8 weeks after CRT completion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response rate | The rate of pathologic complete response rate after neoadjuvant chemoradiotherapy. | Three working days after surgery | 

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 disease-free survival | The 2-year disease-free survival of the whole group | From date of surgery until the date of death from any cause or the date of first documented disease progression whichever came first, assessed up to 24 months. | 
| Incidence of Treatment-related Adverse Events as Assessed by CTCAE v4.0 | The neoadjuvant treatment-related adverse events | From the enrollment to the date of surgery | 
| R0 resection rate | The R0 resection rate of esophagectomy | Three working days after surgery | 
| Perioperative complication rate | The perioperative complication rate of esophagectomy | From date of surgery to 30 days later | 
| Perioperative mortality | The perioperative mortality of esophagectomy | From date of surgery to 30 days later | 

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