Clinical trial NCT06086457: PD-1 Inhibitor Plus Chemotherapy With or Without Radiotherapy in Patients With Metastatic Esophageal Cancer
Official title: PD-1 Inhibitor Plus Chemotherapy With or Without Radiotherapy in Patients With Metastatic Esophageal Cancer: A Randomized Multicenter Phase III Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Esophageal Neoplasms
Keywords: Radiotherapy
PD-1 inhibitor
Lead sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Sponsor class: OTHER
Collaborators: name: Peking University Cancer Hospital & Institute
name: Beijing Cancer Prevention & Treatment Society
name: Hebei Medical University Fourth Hospital
name: Tianjin Medical University Cancer Institute and Hospital
name: Fujian Cancer Hospital
name: Anyang Tumor Hospital
name: The First Affiliated Hospital with Nanjing Medical University
name: Sichuan Cancer Hospital and Research Institute
name: Tengzhou Central People's Hospital
name: The First Affiliated Hospital of Xiamen University
name: The First Affiliated Hospital of Zhengzhou University
name: First Affiliated Hospital Xi'an Jiaotong University
name: Second Affiliated Hospital of Xi'an Jiaotong University
name: Afﬁliated Hospital of North Sichuan Medical College
name: Changzhou Cancer Hospital of Soochow University
name: Henan Cancer Hospital
First posted: 2023-10-17
Enrollment: 436
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 III clinical trial to assess whether radiotherapy with concurrent chemotherapy and immunotherapy could further improve the survival of patients with metastatic esophageal cancer.

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.

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 advanced EC.

As reported, for the patients with metastatic lung cancer or EC, locoregional radiotherapy could improve survival. 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 some patients with advanced EC improve local control, relieve the local symptoms and improving the quality of life.

Therefore, the investigators intend to conduct a prospective, multicenter phase III trial to assess the efficiency and safety of radiotherapy with chemotherapy and immunotherapy of 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.

Eligibility criteria: 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 American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th Edition) , with distant metastasis involving no more than 2 organs (lymph node metastasis is counted);
* 3. ECOG (Eastern Cooperative Oncology Groupper) formance 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.No prior history of thoracic radiation;
* 6.Expected survival is more than 12 weeks;
* 7.Informed consent provided.

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.

Primary outcomes:
measure: Overall survival (OS)
timeFrame: Up to approximately 33 months (through Primary Analysis cut-off date of 30-May-2026).
Secondary outcomes:
measure: Progression-free survival (PFS)
timeFrame: Up to approximately 33 months (through Primary Analysis cut-off date of 30-May-2026).
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 33 months (through Primary Analysis cut-off date of 30-May-2026).
measure: Acute toxicity Rate
timeFrame: One month within the end of one specific treatment.
measure: Late toxicity rate
timeFrame: One month after the end of one specific treatment.
measure: QUALITY OF LIFE: Change From Baseline in the EORTC QLQ-C30 Subscale Score in Participants
timeFrame: 24 months
measure: QUALITY OF LIFE: Change From Baseline in the EORTC QLQ-OES18 Subscale Score in Participants
timeFrame: 24 months
Other outcomes:
measure: Biomarkers for the predicting of efficacy
timeFrame: 33 months
Locations:
city: Beijing
country: China
facility: Cancer hospital, CAMS
state: Beijing
Study officials:
affiliation: Peking University Cancer Hospital & Institute
name: Lin Shen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
name: Wen-Yang Liu, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.