Combination of Toripalimab and Chemoradiotherapy in Esophageal Cancer

• ClinicalTrials.gov Identifier: NCT04005170
• Recruitment Status: Completed
• First Posted: July 2, 2019
• Last Update Posted: August 23, 2022
• Sponsor: Mian XI
• Information provided by (Responsible Party): Mian XI, Sun Yat-sen University

Tracking Information

• First Submitted Date: June 26, 2019
• First Posted Date: July 2, 2019
• Last Update Posted Date: August 23, 2022
• Actual Study Start Date: June 25, 2019
• Actual Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 30, 2019)

clinical complete response rate [ Time Frame: 3 months after chemoradiotherapy (plus or minus 14 days) ]

Tumor response was evaluated 3 months after the completion of chemoradiotherapy based on CT or PET-CT scans, endoscopy with biopsies.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 30, 2019)

• 2-year overall survival [ Time Frame: 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 ]
  The 2-year overall survival of the whole group
• 2-year progression-free survival [ Time Frame: 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 ]
  The 2-year progression-free survival of the whole group
• Duration of response [ Time Frame: From date of first CR/PR to the date of first PD according to RECIST criteria, assessed up to 24 months ]
  Tumor response was evaluated every two months after chemoradiotherapy according to RECIST criteria
• Incidence of treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: From the start of treatment to 2 year after the completion of treatment ]
  Toxicity of treatment was evaluated according to CTCAE 4.0

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: June 30, 2019)

• The impact of PD-L1 expression on clinical response [ Time Frame: Baseline biopsies of primary tumor in esophagus ]
  To investigate the impact of programmed cell death-ligand 1 (PD-L1) expression on clinical response
• The impact of IDO1 expression on clinical response [ Time Frame: Baseline biopsies of primary tumor in esophagus ]
  To investigate the impact of indoleamine 2,3-dioxygenase 1 (IDO1) expression on clinical response

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Combination of Toripalimab and Chemoradiotherapy in Esophageal Cancer
• Official Title: A Phase II Trial of Combination of Toripalimab and Definitive Chemoradiotherapy in Esophageal Squamous Cell Carcinoma
• Brief Summary: 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Unresectable Esophageal Cancer

Intervention

• Drug: Toripalimab
  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.
  Other Name: JS-001
• Drug: Paclitaxel/Cisplatin
  Patients received 5 cycles of paclitaxel/cisplatin (paclitaxel 50mg/m2 and cisplatin 25 mg/m2) on days 1, 8, 15, 22, 29 during radiotherapy.
  Other Name: TP
• Radiation: Intensity-modulated radiotherapy
  All patients received external-beam radiation using intensity-modulated radiotherapy. The prescribed dose is 50.4 Gy in 28 fractions over 5-6 weeks.
  Other Name: IMRT

Study Arms

Experimental: PD-1 group

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.

Interventions:

• Drug: Toripalimab
• Drug: Paclitaxel/Cisplatin
• Radiation: Intensity-modulated radiotherapy

Publications *

• Fu J, Wang F, Dong LH, Zhang J, Deng CL, Wang XL, Xie XY, Zhang J, Deng RX, Zhang LB, Wu H, Feng H, Chen B, Song HF. Preclinical evaluation of the efficacy, pharmacokinetics and immunogenicity of JS-001, a programmed cell death protein-1 (PD-1) monoclonal antibody. Acta Pharmacol Sin. 2017 May;38(5):710-718. doi: 10.1038/aps.2016.161. Epub 2017 Mar 20.
• Tang B, Yan X, Sheng X, Si L, Cui C, Kong Y, Mao L, Lian B, Bai X, Wang X, Li S, Zhou L, Yu J, Dai J, Wang K, Hu J, Dong L, Song H, Wu H, Feng H, Yao S, Chi Z, Guo J. Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients. J Hematol Oncol. 2019 Jan 14;12(1):7. doi: 10.1186/s13045-018-0693-2.
• Zhou S, Zhao L, Liang Z, Liu S, Li Y, Liu S, Yang H, Liu M, Xi M. Indoleamine 2,3-dioxygenase 1 and Programmed Cell Death-ligand 1 Co-expression Predicts Poor Pathologic Response and Recurrence in Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy. Cancers (Basel). 2019 Feb 1;11(2):169. doi: 10.3390/cancers11020169.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 30, 2019): 42
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: July 31, 2022
• Actual Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histologically confirmed squamous cell carcinoma of the esophagus;
2. Absence of hematogenous metastasis disease, confirmed by endoscopic ultrasound (EUS) and PET-CT scan (according to UICC TNM version 8);
3. Not suitable for surgery (either for medical reasons or patient's choice);
4. Age at diagnosis 18 to 70 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 at diagnosis;
3. Known or suspected allergy or hypersensitivity to monoclonal antibodies, any ingredients of Toripalimab, and the chemotherapeutic drugs paclitaxel or cisplatin;
4. Patients who have a preexisting or coexisting bleeding disorder;
5. Female patients who are pregnant or lactating;
6. Inability to provide informed consent due to psychological, familial, social and other factors;
7. Presence of CTC grade ≥ 3 peripheral neuropathy;
8. A history of malignancies other than esophageal cancer before enrollment, excluding non-melanoma skin cancer, in situ cervical cancer, or cured early prostate cancer
9. A history of diabetes for more than 10 years and poorly controlled blood glucose levels;
10. Patients who cannot tolerate chemoradiotherapy due to severe cardiac, lung, liver or kidney dysfunction, or hematopoietic disease or cachexia.
11. 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;
12. A history of interstitial lung disease or non-infectious pneumonia;
13. 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;
14. 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT04005170
• Other Study ID Numbers: TORIDEFEC
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Mian XI, Sun Yat-sen University
• Original Responsible Party: Same as current
• Current Study Sponsor: Mian XI
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Sun Yat-sen University
• Verification Date: August 2022