Neoadjuvant Immunochemotherapy for Adenocarcinoma of the Esophagogastric Junction (TRACE)

June 28, 2024 updated by: Zhigang Li, Shanghai Chest Hospital

Tislelizumab Combined With Chemotherapy as Neoadjuvant Regimen for AdenoCarcinoma of the Esophagogastric Junction: a Single-arm, Phase II Clinical Trial (TRACE)

The investigators will conduct a prospective phase 2 study to evaluate the efficacy and safety of a modified neoadjuvant immunotherapy plus chemotherapy (one cycle of Tislelizumab monotherapy followed by four cycles of Tislelizumab plus Docetaxel, Oxaliplatin and Capecitabine) in patients with locally advanced resectable adenocarcinoma of the esophagogastric junction (AEG).

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Adenocarcinoma of the esophagogastric junction (AEG) has recently garnered increasing attention as a distinct type of malignancy. The World Health Organization (WHO) defines AEG as adenocarcinoma with its center located within 5 cm above or below the esophagogastric junction, crossing or abutting this junction (PMID: 31433515). Surgery remains the primary treatment for locally advanced AEG, but numerous studies have demonstrated that multimodal therapies, such as neoadjuvant chemoradiotherapy and chemotherapy, can achieve better outcomes.

The CROSS study (PMID: 22646630) established neoadjuvant chemoradiotherapy as the standard treatment for resectable esophageal and esophagogastric junction cancers. This trimodal approach not only significantly increased the R0 resection rate but also improved overall survival (OS). The FLOT4 study (PMID: 30982686) compared the efficacy and safety of perioperative FLOT chemotherapy with perioperative ECF chemotherapy in treating gastric cancer/AEG. The study found that the R0 resection rate was significantly higher in the FLOT group compared to the ECF/ECX group (85% vs. 78%). Patients in the FLOT group had a median OS of 50 months, compared to 35 months in the ECX/ECF group, demonstrating that intensified perioperative systemic therapy enhances neoadjuvant efficacy. Despite these advances, the overall prognosis for locally advanced AEG remains poor, with a 5-year survival rate of less than 45%. Thus, there is an urgent need for new treatment strategies to further improve perioperative chemotherapy outcomes for AEG.

Currently, immunotherapy combined with chemotherapy has become the first-line standard treatment recommendation for advanced esophageal cancer/AEG (CheckMate649, PMID: 34102137; Rationale 305, PMID: 38806195). In exploring perioperative immunotherapy for AEG, results from two global Phase III randomized controlled trials (KEYNOTE-585 (PMID: 38134948) and MATTERHORN (2023 ESMO. Abstract #LBA73)) indicated that neoadjuvant immunotherapy combined with chemotherapy significantly increased the pathological complete response rate (pCR) in AEG patients compared to neoadjuvant chemotherapy alone (13% vs. 2% and 17% vs. 7%, respectively). Furthermore, the neoadjuvant immunotherapy combined with chemotherapy groups did not show an increase in adverse events during the neoadjuvant period compared to the neoadjuvant chemotherapy alone groups (64% vs. 63% and 58% vs. 56%, respectively). However, the improvement in overall survival prognosis remains insufficient, suggesting the need to further optimize neoadjuvant immunotherapy protocols to achieve better therapeutic benefits.

The way for optimizing the treatment strategy for immune-chemotherapy includes the modifications of dose, drug selection, number of cycles, schedule and sequencing (PMID: 33712487). The PANDA study, initiated by Dutch researchers, is a single-arm Phase II clinical trial that enrolled 21 patients with resectable AEG (PMID: 38191613). The neoadjuvant treatment involved one induction cycle of single-agent immunotherapy (atezolizumab) followed by four cycles of sequential immunotherapy combined with DOC chemotherapy before surgery. The postoperative pCR rate was 45%, and the major pathological response (MPR) rate was 70% (13 out of 14 MPR patients achieved disease-free survival for up to four years). This study demonstrated that the initial induction with single-agent immunotherapy significantly altered the tumor immune microenvironment, inducing an immune activation state that provided a critical foundation for the efficacy of subsequent sequential immunotherapy combined with chemotherapy. The results suggest that an initial induction with single-agent immunotherapy prior to immunotherapy combining chemotherapy is a superior neoadjuvant immuno-chemotherapy strategy for resectable locally advanced AEG, warranting further exploration and validation in larger cohorts of AEG patients.

However, for Asia, particularly China, given the large base of esophageal cancer cases and the rising incidence of esophageal adenocarcinoma, exploring optimal neoadjuvant treatment strategies for resectable AEG patients in China has become a critical clinical issue.

This study aims to investigate the efficacy and safety of neoadjuvant immunotherapy induction followed by sequential immune-chemotherapy in patients with locally advanced AEG.

Study Type

Interventional

Enrollment (Estimated)

34

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
    • Shanghai
      • Shanghai, Shanghai, China, 200030
        • Shanghai Chest Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Subjects signed the informed consent and volunteered to participate in the study.
  2. Primary resectable, histologically confirmed Adenocarcinoma of the Esophagogastric junction (clinical stage T1-T4aN1-3M0 or T3-T4aN0M0, AJCC 8th).
  3. Expect to have R0 resection
  4. Age 18 or older.
  5. ECOG PS: 0~1.
  6. Have not received any anti-tumor treatment for esophageal cancer in the past, including radiotherapy, chemotherapy, surgery, etc.
  7. No contraindications to surgery.
  8. Has sufficient organ function.
  9. Women of childbearing age must undergo a serological pregnancy test within 7 days before first administration. Women of childbearing age, or male subjects with childbearing age female partners, must take contraceptive measures from the first dose to six months after last administration.
  10. Good compliance, willing to comply with follow-up schedules.

Exclusion Criteria:

1. Subjects have received or are receiving any of:

  1. anti-tumor interventions such as radiotherapy, chemotherapy, immunotherapy or other medications.
  2. Received systemic corticosteroid therapy (prednisone equivalence> 10mg/d) or other immunosuppressive agents within the first 2 weeks prior to the first administration.
  3. live vaccine within 4 weeks before the first administration.

2. Cancer related exclusion criteria:

  1. other cancers instead of AEG
  2. non-resectable or metastatic AEG
  3. Subjects with other malignant tumors within 5 years before the first administration, but subjects with cervical carcinoma in situ, skin basal cell carcinoma, skin squamous cell carcinoma, and localized prostate cancer received radical surgery in situ that have received radical treatment and do not need other treatment can be included.

3. Other criteria: Subjects have uncontrolled cardiovascular diseases, such as 1) heart failure ≥ NYHA class 2, 2) unstable angina 3) myocardial infarction within 1 year; 4) supraventricular or ventricular arrythmia that needs treatment Subjects with any known active autoimmune disease Pregnant or breastfeeding female Presence of allergy or hypersensitivity to investigational medications HIV positive or active hepatitis B (HbsAg positive and HBV-DNA ≥2000 IU/ml or ≥ 104 copies/mL) or active hepatitis C (HCV antibody positive) or active tuberculosis Investigators assessed there might be other factors that cause subjects to withdrawal.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: neoadjuvant anti-PD-1 with DOC chemotherapy
Drug: Immuno-chemotherapy. Patients will receive neoadjuvant therapy (one cycle of Tislelizumab monotherapy followed by four cycles of Tislelizumab plus Docetaxel, Oxaliplatin and Capecitabine) followed by the esophagectomy.
Drug: neoadjuvant anti-PD-1 with DOC chemotherapy

Patients were treated with one cycle of Tislelizumab 200 mg monotherapy on day

1. At 3 weeks and with intervals of 3 weeks between each cycle (weeks 3, 6, 9 and 12), patients received a total of four combination cycles consisting of Tislelizumab 200 mg, docetaxel 50 mg m-2 and oxaliplatin 100 mg m-2 intravenously at the beginning of each cycle, plus oral capecitabine 850 mg m-2 twice daily on days 1-14 of each cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
pCR rate
Time Frame: Through the study completion, an average of 12 months
The primary endpoint is a pCR rate, which is defined as the absence of any remaining tumor cells in both the main tumor and the nearby lymph nodes (ypT0N0) as per the AJCC 8th Edition TRG scoring system
Through the study completion, an average of 12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse events and treatment-related adverse events
Time Frame: Through the study completion, an average of 12 months
Including adverse events and complications. Incidence of adverse events using CTCAE 5.0; grade 3 treatment-related adverse events and higher-grade will be reported
Through the study completion, an average of 12 months
R0 resection rate
Time Frame: Through the study completion, an average of 12 months
A R0 resection rate is defined as the rate of complete tumor removal with negative resection margin microscopically
Through the study completion, an average of 12 months
MPR rate
Time Frame: Through the study completion, an average of 12 months
The primary endpoint is a pCR rate, which is defined as the absence of any remaining tumor cells in both the main tumor and the nearby lymph nodes (ypT0N0) as per the AJCC 8th Edition TRG scoring system
Through the study completion, an average of 12 months
Event-free survival (EFS)
Time Frame: Through the study completion, an average of 36 months
An event-free survival (EFS) is defined as the duration from the start of treatment until disease progression/recurrence or death from any cause, whichever occurs first
Through the study completion, an average of 36 months
Overall survival (OS)
Time Frame: Through the study completion, an average of 36 months
Overall survival (OS) is defined as the time from treatment to death, regardless of disease recurrence
Through the study completion, an average of 36 months
2-year recurrence-free survival between patients with postoperative ctDNA negative and postoperative ctDNA positive
Time Frame: From the completion of surgery to the completion of the 2-year postoperative follow-up.
patients will have ctDNA detection at 2-4 weeks after surgery
From the completion of surgery to the completion of the 2-year postoperative follow-up.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Shanghai Chest Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

June 19, 2024

Primary Completion (Estimated)

June 30, 2025

Study Completion (Estimated)

June 30, 2027

Study Registration Dates

First Submitted

June 16, 2024

First Submitted That Met QC Criteria

June 16, 2024

First Posted (Actual)

June 21, 2024

Study Record Updates

Last Update Posted (Actual)

July 1, 2024

Last Update Submitted That Met QC Criteria

June 28, 2024

Last Verified

June 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SCE2403

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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