Radiotherapy in Patients With Metastatic Esophageal Cancer Responding to PD-1 Inhibitor Plus Chemotherapy

Radiotherapy in Patients With Metastatic Esophageal Cancer Responding to PD-1 Inhibitor Plus Chemotherapy: a Patient Preference Multicenter Randomized Phase II Trial

The treatment efficacy for stage IVb esophageal cancer has been improved through chemotherapy combined with immunotherapy recently.

On this basis, the investigators intend to conduct a prospective, multicenter phase II clinical trial to assess whether radiotherapy could further improve the survival of patients with metastatic esophageal cancer responding to PD-1 Inhibitor plus chemotherapy.

Accompanied tissue samples, blood samples and urine samples will be analyzed by molecular biological detection (Including Whole Exome Sequencing and proteomics) to explore potential biomarkers for predicting outcomes, efficacy and toxicity.

Study Overview

• Status: Recruiting
• Conditions: Esophageal Neoplasm Metastatic; Esophageal Cancer Stage IVb
• Intervention / Treatment: Drug: TP (Paclitaxel with cisplatin or carboplatin) or PF (Fluoropyrimidine with cisplatin or carboplatin) regimen depended on investigator's choice.; Radiation: Consolidation Radiation; Biological: PD-1 inhibitor; Radiation: Salvage Radiation

Detailed Description

Esophageal cancer (EC) is one of the most common carcinomas with high morbidity and mortality worldwide. More than 30% of the patients were stage IV when diagnosed. Fluoropyrimidine plus platinum-based chemotherapy is recommended as first-line treatment for patients with metastatic EC for approximately four decades, however, only minimal improvement has been reached in overall survival (OS).

Recently, immune checkpoint inhibitors have shown effective antitumor activity in patients with unresectable, advanced or metastatic EC. Several randomized trials have demonstrated the PD-1 inhibitor could further improve the OS in patients with advanced esophageal squamous cell carcinoma (ESCC) on the basis of chemotherapy. Chemotherapy combined with immunotherapy has become one of the the standard treatment modality for metastatic EC.

As reported, for the patients with metastatic lung cancer or EC, locoregional radiotherapy could improve survival, especially in those who responding to systemic therapy. However, high-level evidence is still needed to assess whether these patients can benefit from local radiotherapy.

The efficacy of immunotherapy combined with chemotherapy is obviously better than that of chemotherapy alone. On this basis, locoregional radiotherapy may help those patients with metastatic EC responding to systemic therapy improve local control, relieve the local symptoms, and even improve survival.

Therefore, the investigators intend to conduct a prospective, multicenter phase II trial to assess the efficiency and safety of radiotherapy with chemotherapy and immunotherapy for patients with metastatic EC. Accompanied tissue samples, blood samples and urine samples will be analyzed by molecular biological detection to explore potential biomarkers for predicting outcomes, efficacy and toxicity.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Wen-Yang Liu, MD; Phone Number: 8601087787625; Email: liuwenyang@cicams.ac.cn

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100021
      • Recruiting
      • Cancer hospital, CAMS
      • Contact: Wen-Yang Liu, MD; Email: liuwenyang@cicams.ac.cn
      • Contact: Email: liuwenyang@cicams.ac.cn
      • Principal Investigator: Wen-Yang Liu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1. ≥18 years, any gender
• 2. Histologically or cytologically confirmed squamous cell carcinoma of esophageal cancer. The initial clinical stage is IVb (2018 AJCC Cancer Staging Manual, 8th Edition) or recurrent patients with recurrence after radical treatment (radical treatment includes surgery and radiotherapy, but the recurrence site cannot be located in the previous radiotherapy field).
• 3. ECOG performance status <= 1. Patients aged 65 years and over need to complete G8 screening or Comprehensive Geriatric Assessment, and the final evaluation is good;
• 4.There was no significant abnormality in laboratory routine indicators such as blood routine and liver and kidney function;
• 5.For patients after definitive or preoperative radiotherapy, no recurrence was in the prior radiation filed;
• 6.Expected survival is more than 12 weeks;
• 7.Informed consent provided;
• 8.With response to 2-4 cycles of the first-line chemotherapy combined with immunotherapy.

Exclusion Criteria:

• 1.Patients with other cancer history except hypopharyngeal carcinoma in situ, non-malignant skin cancer and cervical carcinoma in situ.
• 2.Received surgery (except ostomy), chemotherapy or other anti-tumor treatment before enrollment；
• 3. Active infection currently exists . The following conditions occurred within 6 months before randomization: myocardial infarction, cerebrovascular accident, or received gastrointestinal, neurological, cardiopulmonary surgery;
• 4. History of allergy to chemotherapy drugs or autoimmune disease;
• 5. Participate in other clinical trials at present or within 4 weeks before enrollment;
• 6.There are factors such as high risk of fistula that radiotherapy cannot be safely carried out as assessed by the radiation oncologist.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Consolidation radiotherapy; This treatment group will be receive radiotherapy on the basis of standard first-line treatment, after all planned cycles of chemotherapy combined with PD-1 inhibitor completed.	Drug: TP (Paclitaxel with cisplatin or carboplatin) or PF (Fluoropyrimidine with cisplatin or carboplatin) regimen depended on investigator's choice.; A maximum of six cycles was recommended for chemotherapy.; Fluoropyrimidine (fluorouracil or capecitabine) with carboplatin or cisplatin;; Paclitaxel (or Albumin-bound paclitaxel) with carboplatin or cisplatin.; Other Names: Chemotherapy; Radiation: Consolidation Radiation; IMRT/VMAT technique. Patients receive radiotherapy once daily, 5 days a week for an average of 5 weeks. Radiotherapy is delivered to achieve a dosage of 49.22Gy/23f or 50Gy/25f to PGTV for lymphnode metastasis only patients and 40.66Gy/19f or 40Gy/20f for organ metastasis patients. Radiation treatment is planned after chemotherapy completed.; Other Names: Planned Radiotherapy; Biological: PD-1 inhibitor; Nivolumab or Pembrolizumab or Tislelizumab or Serplulimab or Toripalimab or Sintilimab or Camrelizumab; Other Names: Immunotherapy
Experimental: Salvage radiotherapy; This treatment group will be receive salvage radiotherapy on the basis of standard first-line treatment, when disease progressed and salvage radiotherapy is recommended by multidisciplinary team.	Drug: TP (Paclitaxel with cisplatin or carboplatin) or PF (Fluoropyrimidine with cisplatin or carboplatin) regimen depended on investigator's choice.; A maximum of six cycles was recommended for chemotherapy.; Fluoropyrimidine (fluorouracil or capecitabine) with carboplatin or cisplatin;; Paclitaxel (or Albumin-bound paclitaxel) with carboplatin or cisplatin.; Other Names: Chemotherapy; Biological: PD-1 inhibitor; Nivolumab or Pembrolizumab or Tislelizumab or Serplulimab or Toripalimab or Sintilimab or Camrelizumab; Other Names: Immunotherapy; Radiation: Salvage Radiation; IMRT/VMAT technique. Patients receive radiotherapy once daily, 5 days a week for an average of 5 weeks. Radiotherapy is delivered to achieve a dosage of 49.22Gy/23f or 50Gy/25f to PGTV for lymphnode metastasis only patients and 40.66~49.22Gy/19f ~23f or 40~50Gy/20~25f for organ metastasis patients. Radiation treatment is planned after disease progression when recommended by multidisciplinary team.; Other Names: Radiotherapy when needed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EFFICACY:1-year overall survival probability	Overall survival was defined as the time from first dose to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. OS is reported for all participants of the Intent-To-Treat (ITT) population. The Kaplan-Meier method was used to calculated the 1-year survival probability.	12 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EFFICACY: Median progression-free survival (PFS)	Median progression-free survival (PFS), was defined as the time from first dose to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, or death due to any cause, whichever occurred first.	12 month
SAFETY: Acute toxicity rate	Acute toxicity Rate, was defined as the frequency of toxicities related to the treatment, which arises within one month after administration, according to National Cancer Institute Common Terminology Criteria for Adverse Event,Version 5.0 (CTC AE5.0).	One month within the end of one specific treatment
SAFETY: Late toxicity rate	Late toxicity rate, was defined as the frequency of toxicities related to the treatment, which arises after one month after administration, according to National Cancer Institute Common Terminology Criteria for Adverse Event,Version 5.0 (CTC AE5.0).	One month after the end of one specific treatment.
QUALITY OF LIFE: Change From Baseline in the EORTC QLQ-C30 Subscale Scores in Participants	The score of the participants evaluated by The EORTC core quality of life questionnaire (QLQ-C30). All of the scales and single-item measures range in score from 0 to100.A high scale score represents a higher response level. Thus a high score for a functional scale represents a high/healthy level of functioning.	24 month
QUALITY OF LIFE: Change From Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants	The score of the participants evaluated by The EORTC Quality of Life Questionnaire - Oesophageal Cancer Module (EORTC QLQ-OES18). All of the scales and single-item measures range in score from 0 to100.A high scale score represents a higher response level. Thus a high score for a functional scale represents a high/healthy level of functioning.	24 month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers for the predicting of efficacy	To explore the dynamic changes of circulating tumor DNA (the frequency of specific mutations by Next-generation sequencing Methodology) from baseline, before and after radiotherapy.	24 month

Collaborators and Investigators

• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Collaborators: Peking University Cancer Hospital & Institute; Tianjin Medical University Cancer Institute and Hospital; Hebei Medical University Fourth Hospital; Anyang Tumor Hospital
• Investigators: Principal Investigator: Wen-Yang Liu, MD, Cancer Institute and Hospital, Chinese Academy of Medical Sciences; Principal Investigator: Zhi-Hao Lu, MD, Peking University Cancer Hospital & Institute

Publications and helpful links

General Publications

• Guttmann DM, Mitra N, Bekelman J, Metz JM, Plastaras J, Feng W, Swisher-McClure S. Improved Overall Survival with Aggressive Primary Tumor Radiotherapy for Patients with Metastatic Esophageal Cancer. J Thorac Oncol. 2017 Jul;12(7):1131-1142. doi: 10.1016/j.jtho.2017.03.026. Epub 2017 Apr 28.
• Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, Kojima T, Metges JP, Li Z, Kim SB, Cho BC, Mansoor W, Li SH, Sunpaweravong P, Maqueda MA, Goekkurt E, Hara H, Antunes L, Fountzilas C, Tsuji A, Oliden VC, Liu Q, Shah S, Bhagia P, Kato K; KEYNOTE-590 Investigators. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021 Aug 28;398(10302):759-771. doi: 10.1016/S0140-6736(21)01234-4. Erratum In: Lancet. 2021 Nov 20;398(10314):1874.
• Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, Li J, Fu Z, Gu K, Liu Z, Wu L, Zhang X, Feng J, Niu Z, Ba Y, Zhang H, Liu Y, Zhang L, Min X, Huang J, Cheng Y, Wang D, Shen Y, Yang Q, Zou J, Xu RH; ESCORT-1st Investigators. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA. 2021 Sep 14;326(10):916-925. doi: 10.1001/jama.2021.12836.

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2023
• Primary Completion (Estimated): April 26, 2026
• Study Completion (Estimated): October 26, 2028

Study Registration Dates

• First Submitted: September 19, 2023
• First Submitted That Met QC Criteria: October 12, 2023
• First Posted (Actual): October 16, 2023

Study Record Updates

• Last Update Posted (Actual): June 14, 2024
• Last Update Submitted That Met QC Criteria: June 12, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Carboplatin; Paclitaxel; Cisplatin; Immune Checkpoint Inhibitors
• Other Study ID Numbers: BEIR 1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data obtained through this study may be provided to qualified researchers with academic interest in esophageal cancer. Data or samples shared will be coded, with no PHI included. Approval of the request and execution of all applicable agreements (i.e. a material transfer agreement) are prerequisites to the sharing of data with the requesting party.
• IPD Sharing Time Frame: Data requests can be submitted starting 12 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis
• IPD Sharing Access Criteria: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information or to submit a request, please contact liuwenyang@cicams.ac.cn
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No