Neoadjuvant Immunochemotherapy for Adenocarcinoma of the Esophagogastric Junction

NCT ID: NCT06469060

Last Updated: 2024-07-01

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-06-19
• Study Completion Date: 2027-06-30

Brief Summary

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).

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.

Conditions

Esophageal Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

neoadjuvant anti-PD-1 with DOC chemotherapy

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shanghai Chest Hospital

OTHER

Sponsor Role: lead

Responsible Party

Zhigang Li

Chief of Department of Thoracic Surgery

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Shanghai Chest Hospital

Shanghai, Shanghai Municipality, China

Countries

China

Central Contacts

Zhigang Li, MD, PhD

Role: CONTACT

zhigang.li@shsmu.edu.cn

+86-18960619260

Zhichao Liu, MD, PhD

Role: CONTACT

liuzc1995@163.com

+86-15622175948

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Other Identifiers

SCE2403

Identifier Type: -

Identifier Source: org_study_id