Efficacy and Safety of Concurrent PD-1 Inhibitor and Radiotherapy With Immunonutrition for Esophageal Squamous Cell Carcinoma

Radiotherapy Clinical Trial

Official title:

Efficacy and Safety of Concurrent Sintilimab and Radiotherapy With Immunonutrition Support in Esophageal Cancer: A Phase II Multicenter Clinical Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT06342167
• Other study ID #: NCC4409
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: March 14, 2024
• Est. completion date: December 1, 2026

Study information

• Verified date: April 2024
• Source: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

At present, concurrent chemoradiotherapy (cCRT) with platin-based dual-drug regimen is the standard treatment for inoperable, locally advanced esophageal cancer in patients with a good performance status. However, cCRT has substantial toxic effects, and a large number of patients with older age, malnutrition and other morbidities, cannot tolerate cCRT. Several phase II trials showed combining PD-1 inhibitor with definitive cCRT provided encouraging activity and acceptable toxicity in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). Therefore, this single-arm, multicenter, phase II trial aims to assess the efficacy and safety of immunotherapy plus radiotherapy with immunonutrition support in patients with LA-ESCC and positive PD-L1 expression who are intolerant to cCRT.

Description:

This single-arm trial is designed to evaluate the efficacy and safety of concurrent immunotherapy (sintilimab) plus radiotherapy with immunonutrition support (enteral nutritional emulsion (TPF-T) followed by consolidation immunotherapy in patients with LA-ESCC and PD-L1 positive expression who are intolerant to cCRT. The eligible patients will receive concurrent treatment consisting of total dose of 50-50.4 Gy in 25-28 fractions and 200 mg of sintilimab administered every three weeks, along with enteral nutritional emulsion (TPF-T) support (600-1600 ml per day according to the nutrition status evaluation). The primary outcome is 1-year progression-free survival (PFS) rate. The investigators hypothesized PD-L1 inhibitor plus radiotherapy will improve the 1-year PFS from 40% to 60%. Then, 58 patients will be needed in total. The secondary outcomes will include objective response rate (ORR), overall survival (OS), progression-free and overall survival, and incidence of adverse events. This study is approval by the National GCP Center for Anticancer Drugs, Independent Ethics Committee, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College (Study ID: 24/074-4354).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 57
• Est. completion date: December 1, 2026
• Est. primary completion date: July 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Aged 18 years or order.

2. Diagnosed with locally advanced esophageal squamous cell carcinoma by pathological examinations of the primary lesion and imaging examinations.

3. Confirmed to be unresectable and unable to tolerate synchronous chemoradiotherapy by multidisciplinary consultation, and has not undergone systemic drug therapy in the past.

4. A PD-L1 tumor proportion score (PD-L1 IHC 22C3 pharmDx) of =1%.

5. At least one measurable lesion on imaging according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

6. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 -2.

7. Expected survival time of more than three months.

8. Adequate organ function defined as the following laboratory indicators:

1. Absolute neutrophil count (ANC) = 1.5×109/L without use of granulocyte colony-stimulating factor in the past 14 days.

2. Platelet count = 100×109/L without blood transfusion in the past 14 days.

3. Hemoglobin > 9g/dL without blood transfusion or use of erythropoietin-stimulating agents in the past 14 days.

4. Total bilirubin = 1.5×upper limit of normal (ULN).

5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5×ULN.

6. Creatinine = 1.5×ULN and creatinine clearance calculated using the Cockcroft-Gault formula) = 60 ml/min.

7. Good coagulation function, defined as an international normalized ratio (INR) or prothrombin time (PT) = 1.5×ULN.

8. Normal thyroid function, defined as thyroid-stimulating hormone (TSH) within the normal range. If the baseline TSH is outside the normal range, subjects with total T3 (or FT3) and FT4 within the normal range can still be included.

9. Normal cardiac enzyme spectrum (or clinically insignificant laboratory abnormalities as determined by the investigator)

9. Negative pregnancy test (urine or serum) within 3 days before the first dose of study drug for female subjects of childbearing potential. If the urine pregnancy test cannot be confirmed as negative, a blood pregnancy test is required. Non-childbearing potential female is defined as postmenopausal for at least 1 year or has undergone surgical sterilization or hysterectomy.

10. Willing to sign the informed consent form. Exclusion Criteria:

Subjects with any of the following conditions cannot participate in the study:

1. A high risk of bleeding or perforation due to clear invasion of adjacent organs (large arteries or trachea) by the tumor, or with fistula.

2. Diagnosed with malignancies other than esophageal cancer within 3 years prior to the first dose (excluding cured basal cell carcinoma or squamous cell carcinoma of the skin and/or radically resected carcinoma in situ).

3. Previous immunological or immunomodulatory drugs as systemic whole-body treatment, including thymic peptides, interferon, interleukins, except for local use to control pleural effusion.

4. Previous chest radiotherapy.

5. A history of allogeneic organ transplantation (except for corneal transplantation) or allogeneic hematopoietic stem cell transplantation.

6. Allergic to the study drug, Sintilimab, or its excipients.

7. A history of human immunodeficiency virus (HIV) infection (i.e., HIV1/2 antibody positive).

8. Untreated active hepatitis B defined as HBsAg positive and HBV-DNA copy number greater than the upper limit of the normal value in the laboratory of the study center.

Note: Patients with hepatitis B who meet the following criteria can also be included:

1. HBV viral load <1000 copies/ml (200IU/ml) before the first dose; the patient should receive anti-HBV treatment throughout chemotherapy in the entire study to avoid viral reactivation.

2. For patients who are anti-HBc (+), HBsAg (-), anti-HBs (-), and HBV viral load (-), no prophylactic anti-HBV treatment is required, but close monitoring of viral reactivation is needed.

9. Active hepatitis C virus (HCV) infection defined as HCV antibody positive and HCV-RNA levels higher than the detection limit.

10. Having received live vaccines within 30 days prior to the first dose (Cycle 1, Day 1). Note: It is allowed to receive inactivated virus vaccines for seasonal influenza within 30 days prior to the first dose, but attenuated live influenza vaccines administered intranasally are not allowed.

11. Pregnant or lactating women;

12. Any serious or uncontrollable systemic diseases, such as:

1. Significant and symptomatic abnormalities in rhythm, conduction or morphology on resting electrocardiogram, such as complete left bundle branch block, second-degree or higher heart block, ventricular arrhythmia, or atrial fibrillation;

2. Unstable angina, congestive heart failure, or chronic heart failure classified as New York Heart Association (NYHA) class = 2;

3. Any arterial thrombosis, embolism or ischemic events, such as myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack, occurring within 6 months prior to enrollment;

4. Poor blood pressure control defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg;

5. A history of non-infectious pneumonia requiring glucocorticoid therapy within 1 year prior to initial treatment, or current clinical activity of interstitial lung disease;

6. Active pulmonary tuberculosis;

7. Active or uncontrolled infections requiring systemic therapy;

8. Active diverticulitis, abdominal abscess, or gastrointestinal obstruction;

9. Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis;

10. Poorly controlled diabetes (fasting blood glucose (FBG) > 10mmol/L);

11. Urine protein = ++ on routine urinalysis, with confirmed 24-hour urine protein quantification > 1.0 g;

12. Psychiatric disorders that are unable to comply with treatment.

13. Any other medical histories, disease evidence, treatment, or laboratory values that may interfere with the test results, hinder the full participation in the study, or other situations that the investigator deems unsuitable for inclusion due to potential risks.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Squamous Cell
• Concurrent Chemoradiotherapy
• Esophageal Squamous Cell Carcinoma
• Immunonutrition
• Locally Advanced Esophageal Squamous Cell Carcinoma
• Radiotherapy
• Sintilimab

Intervention

Radiation:
• Radiotherapy
Interventions consist of 50-50.4 Gy in 25-28 fractions of radiotherapy.

Drug:
• Programmed Cell Death Protein 1 Inhibitor
200 mg of Sintilimab administered every three weeks concurrently with radiotherapy and after radiotherapy as consolidation therapy up to 1year.

Dietary Supplement:
• Immunonutrition support
600-1600 ml of TPF-T per day according to the nutrition status evaluation

Locations

Country	Name	City	State
China	Department 1st of Radiation Oncology, Anyang Tumor Hospital	Anyang	Henan
China	Department of Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College	Beijing	Beijing
China	Department of Radiation Oncology,Fei County People's Hospital	Feixian	Shandong
China	Department of Radiation Oncology,Clinical Oncology School of Fujian Medical University,Fujian Cancer Hospital	Fujian	Fujian
China	Department of Oncology, Affiliated Hospital, Hebei University of Engineering	Handan	Hebei
China	Department of Radiation Oncology, Affiliated hospital of Jining Medical University	Jining	Shandong
China	Taizhou hospital of Wenzhou Medical University	Taizhou	Zhejiang
China	Department of Radiation Oncology the first affiliated hospital of Xinxiang Medical University	Xinxiang	Henan
China	Department of Radiation Oncology, General Hospital of Ningxia Medical University	Yinchuan	Ningxia

Sponsors (1)

Lead Sponsor	Collaborator
Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Country where clinical trial is conducted

China, 

References & Publications (9)

Chen Y, Ye J, Zhu Z, Zhao W, Zhou J, Wu C, Tang H, Fan M, Li L, Lin Q, Xia Y, Li Y, Li J, Jia H, Lu S, Zhang Z, Zhao K. Comparing Paclitaxel Plus Fluorouracil Versus Cisplatin Plus Fluorouracil in Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Cancer: A Randomized, Multicenter, Phase III Clinical Trial. J Clin Oncol. 2019 Jul 10;37(20):1695-1703. doi: 10.1200/JCO.18.02122. Epub 2019 Mar 28. — View Citation

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Li C, Tan L, Liu X, Wang X, Zhou Z, Chen D, Feng Q, Liang J, Lv J, Wang X, Bi N, Deng L, Wang W, Zhang T, Ni W, Chang X, Han W, Gao L, Wang S, Xiao Z. Concurrent chemoradiotherapy versus radiotherapy alone for patients with locally advanced esophageal squamous cell carcinoma in the era of intensity modulated radiotherapy: a propensity score-matched analysis. Thorac Cancer. 2021 Jun;12(12):1831-1840. doi: 10.1111/1759-7714.13971. Epub 2021 May 5. — View 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. — View Citation

Ohri N, Jolly S, Cooper BT, Kabarriti R, Bodner WR, Klein J, Guha C, Viswanathan S, Shum E, Sabari JK, Cheng H, Gucalp RA, Castellucci E, Qin A, Gadgeel SM, Halmos B. Selective Personalized RadioImmunotherapy for Locally Advanced Non-Small-Cell Lung Cancer Trial (SPRINT). J Clin Oncol. 2024 Feb 10;42(5):562-570. doi: 10.1200/JCO.23.00627. Epub 2023 Nov 21. — View Citation

Park S, Oh D, Choi YL, Chi SA, Kim K, Ahn MJ, Sun JM. Durvalumab and tremelimumab with definitive chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. Cancer. 2022 Jun 1;128(11):2148-2158. doi: 10.1002/cncr.34176. Epub 2022 Mar 23. — View Citation

Tachihara M, Tsujino K, Ishihara T, Hayashi H, Sato Y, Kurata T, Sugawara S, Shiraishi Y, Teraoka S, Azuma K, Daga H, Yamaguchi M, Kodaira T, Satouchi M, Shimokawa M, Yamamoto N, Nakagawa K; West Japan Oncology Group (WJOG). Durvalumab Plus Concurrent Radiotherapy for Treatment of Locally Advanced Non-Small Cell Lung Cancer: The DOLPHIN Phase 2 Nonrandomized Controlled Trial. JAMA Oncol. 2023 Nov 1;9(11):1505-1513. doi: 10.1001/jamaoncol.2023.3309. — View Citation

You J, Zhu S, Li J, Li J, Shen J, Zhao Y, Li X, Jia L, Li Q, Yang J, Wu Y, Shen W, Wu H, Wu X, Wang X, Ren Y, He J, Lin P, Zhu G, Shi A. High-Dose Versus Standard-Dose Intensity-Modulated Radiotherapy With Concurrent Paclitaxel Plus Carboplatin for Patients With Thoracic Esophageal Squamous Cell Carcinoma: A Randomized, Multicenter, Open-Label, Phase 3 Superiority Trial. Int J Radiat Oncol Biol Phys. 2023 Apr 1;115(5):1129-1137. doi: 10.1016/j.ijrobp.2022.11.006. Epub 2022 Nov 17. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	1-year Progression-free survival rate (PFS)	Progression-free survival rate is defined the rate of progress event at 1-years after radiotherapy. Progression event is defined as event of primary tumor and regional recurrence, or distant metastasis	From start of treatment until 1 years of follow-up.
Secondary	Objective response rate	Response is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.	Measured at 3 months after completion of radiotherapy
Secondary	Progression-free survival	Progression-free survival is defined as the time from treatment to the event of primary tumor and regional recurrence, or distant metastasis	Measured at months 6, 12, 18, and 24.
Secondary	Overall survival rate	Live rate at months 6, 12, 18, and 24.	Measured at months 6, 12, 18, and 24.
Secondary	Overall survival	Live status at different time points.	From start of treatment until 3 years of follow-up.
Secondary	Incidence of adverse events	Adverse events are classified according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0) criteria.	Measured at months 6, 12, 18, and 24.