Clinical trial NCT06601309: Biomarker Based Neoadjuvant Strategies for Locally Advanced Resectable ESCC
Official title: Biomarker Based Neoadjuvant Strategies for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma: an Exploratory Phase II Single-arm Clinical Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Esophageal Squamous Cell Carcinoma
Keywords: Esophageal Cancer
Neoadjuvant Therapy
Pathological Complete Response (pCR)
Immunotherapy
Chemoradiotherapy
Biomarkers
Lead sponsor: Fujian Medical University Union Hospital
Sponsor class: OTHER
First posted: 2024-09-19
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: This parallel assignment interventional study evaluates the efficacy and safety of biomarker-based neoadjuvant treatments in resectable locally advanced esophageal squamous cell carcinoma (ESCC). Patients are stratified by PD-L1 expression (CPS) into three groups:

1. High PD-L1 Expression (CPS ≥ 20) Neoadjuvant immunotherapy alone.
2. Moderate PD-L1 Expression (CPS 10-20): Neoadjuvant chemotherapy combined with immunotherapy.
3. Low PD-L1 Expression (CPS \< 10): Standard neoadjuvant chemoradiotherapy.

All treatments are followed by surgical resection. The primary endpoint is the pathological complete response (pCR) rate post-surgery. Secondary endpoints include treatment-related toxicity, R0 resection rate, and 3-year disease-free survival (DFS). Exploratory endpoints include identifying molecular biomarkers linked to treatment efficacy.
Primary purpose: TREATMENT

Brief summary: This study aims to evaluate the impact of the neoadjuvant treatment strategy based on CPS score on the pathological complete response (pCR) rate in patients with resectable locally advanced esophageal cancer.

Detailed description: Esophageal cancer is a malignant tumor with a high incidence in China, with most patients diagnosed at the advanced stage. Traditional treatment modalities include surgery, chemoradiotherapy, and chemotherapy. However, under current standard treatments, approximately 50% of patients remain incurable, primarily due to postoperative recurrence and distant metastasis. Therefore, seeking a new treatment strategy to improve efficacy is crucial.

This clinical trial aims to evaluate the use of immune checkpoint inhibitors in neoadjuvant therapy based on CPS scoring to enhance the pathologic complete response (pCR) rate. Patients pathologically confirmed with esophageal squamous cell carcinoma (ESCC) will undergo surgical assessment for operability. Eligible patients will further undergo CPS testing and will receive different neoadjuvant treatment strategies based on CPS results: patients with CPS ≥20 will receive neoadjuvant immunotherapy alone; CPS 10-20 patients will receive neoadjuvant chemotherapy followed by immunotherapy; and CPS \<10 patients will receive standard neoadjuvant chemoradiotherapy.

After completing neoadjuvant therapy, patients will rest for 4-6 weeks before undergoing curative surgery, which will be reassessed by thoracic surgeons for R0 resection feasibility preoperatively. Postoperatively, pathological evaluation will assess the pCR rate and other secondary study endpoints, with the most severe toxicities included in the analysis.

This study anticipates a group-wide pCR rate of 45% based on a PD-L1 biomarker-guided neoadjuvant treatment strategy. The trial is designed to exclude a pCR rate of 30% or lower using a one-sided 95% confidence interval (α set at 0.025) and 80% statistical power, with a total sample size of 90. The null hypothesis will be rejected if fewer than 34 patients achieve pCR in the entire cohort.

Based on reference studies (EC-CRT-001, ESCORT-1, JUPITER-06, and KEYNOTE-590) and CPS distribution data for esophageal squamous cell carcinoma from our institution, it is expected that the proportions of patients with CPS ≥20, 10-20, and \<10 will be 10%, 40%, and 50%, respectively, corresponding to 9, 36, and 45 eligible patients for each group. It is anticipated that biological specimens will be obtained from more than 30 patients.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis: Histologically confirmed esophageal squamous cell carcinoma (ESCC).
2. Stage: Resectable locally advanced ESCC (clinical stage II-III according to the AJCC/UICC 8th edition).
3. Age: 18-75 years old.
4. Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
5. PD-L1 Expression: Available PD-L1 expression level (CPS).
6. Surgical Eligibility: Assessed as eligible for surgical resection by a thoracic surgeon.
7. Laboratory Requirements:

   * Adequate bone marrow function: Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L, Platelets ≥ 100 x 10\^9/L, Hemoglobin ≥ 9 g/dL.
   * Adequate liver function: Total bilirubin ≤ 1.5 x upper limit of normal (ULN), AST and ALT ≤ 2.5 x ULN.
   * Adequate renal function: Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 mL/min.
8. Informed Consent: Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

1. Distant Metastasis: Presence of distant metastasis.
2. Other Malignancies: History of other malignancies within the past 5 years, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin carcinoma, or other localized non-invasive malignancy.
3. Autoimmune Diseases: History of active autoimmune diseases requiring systemic treatment within the past 2 years.
4. Infections: Active infection requiring systemic therapy.
5. Uncontrolled Conditions: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
6. Previous Treatment: Previous treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies.
7. Pregnancy and Lactation: Pregnant or breastfeeding women. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization.
8. Allergies: Known allergy or hypersensitivity to study drugs or any excipient of these medications.

Primary outcomes:
measure: Pathological Complete Response (pCR) Rate
timeFrame: after the pathological examination of surgical speciments within 14 days after the operation
Secondary outcomes:
measure: R0 Resection Rate
timeFrame: after the pathological examination of surgical speciments ie within 14 days after the operation
measure: Treatment-Related Toxicity
timeFrame: From the start of treatment to 30 days post-surgery
measure: 3-Year Disease-Free Survival (DFS)
timeFrame: 36 months after treatment completion
measure: Tumor Mutational Burden (TMB)
timeFrame: 36 months after treatment completion.
measure: Microsatellite Instability (MSI)
timeFrame: 36 months after treatment completion
measure: Circulating Tumor DNA (ctDNA)
timeFrame: 36 months after treatment completion
Other outcomes:
Locations:
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital
state: Fujian
Study officials:
References: