Concurrent Neoadjuvant Chemoradiotherapy Plus Trastuzumab in the Treatment of Siewert II ，III of Human Epidermal Growth Factor Receptor-2(HER-2) Positive Gastroesophageal Junction Adenocarcinoma： A Randomized, Controlled Clinical Study

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of patients who receive concurrent neoadjuvant chemoradiotherapy for Siewert II ，III of locally advanced HER-2 Positive adenocarcinoma at gastroesophageal junction

Official Title
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A Prospective Study of Concurrent Neoadjuvant Chemoradiotherapy Plus Trastuzumab for Siewert II ，III of HER-2 Positive Adenocarcinoma at Gastroesophageal Junction

Conditions
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Gastroesophageal Junction Adenocarcinoma

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: Capecitabine
* Drug: Oxaliplatin
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age:18 to 60 years old (man or female); confirmed to Siewert II , III of locally advanced adenocarcinoma at gastroesophageal junction. The her-2 positive was detected by immunohistochemistry or Fluorescence in SituHybridization(FISH); Patients with Stage for Ⅲ by Endorectal Ultrasonography( EUS), Computed Tomography(CT) (or Positron Emission Tomography(PET )-CT) and laparoscopic (According to the eighth edition of American Joint Committee on Cancer (AJCC) ); Patients are diagnosed as potentially resectable by multidisciplinary team, no surgical contraindications, and expected to be surgical resection; Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; Major organ function has to meet the following criteria: HB≥80g/L; ANC≥1.5×109/L; PLT≥90×109/L; Alanine Transaminase (ALT) and Aspartate Transaminase(AST)≤2.5×ULN, but<≤5×ULN if the transferase elevation is due to liver metastases； Total Bilirubin(TBIL)<1.5×ULN； Serum creatinine ≤1.5×ULN;Serum albumin ≥ 30g / L Life expectancy greater than or equal to 6 months; Participants were willing to join in this study, and written informed consent, good adherence, cooperate with the follow-up. Exclusion Criteria: Allergic to trastuzumab, capecitabine and oxaliplatin; severe diseases such as liver and kidney，myocardial infarction, symptomatic congestive heart failure (CHF) (NYHA classes II-IV), unstable angina or serious cardiac arrhythmia，which affect the situation of chemotherapy or surgery A variety of factors influencing oral drugs (such as unable to swallow, nausea, vomiting, chronic diarrhea and intestinal obstruction, etc); Patients with tendency of gastrointestinal bleeding, including the following: a local active ulcerative lesions, and defecate occult blood (+ +); Has melena and hematemesis in two months; Coagulant function abnormality (International Normalized Ratio(INR) > 1.5 ULN, Activated Partial Thromboplastin Time(APTT ) > 1.5 ULN), with bleeding tendency; Pregnant or lactating women; Patients with other malignant tumors within 5 years (except for curable skin basal cell carcinoma and cervical carcinoma in situ); History of psychiatric drugs abuse and can't quit or patients with mental disorders; Less than 4 weeks from the last clinical trial; The researchers think inappropriate.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab XELOX and radiotherapy<br>Trastuzumab is intravenously administered with the loading dose of 8 mg/kg followed by maintenance dose of 6mg/kg in day 1 of each cycle. XELOX：Capecitabine 825 1000mg/m2 bid d1-14，Oxaliplatin 130 mg/m2 Ivgtt d1 q3w Radiotherapy：45 Gray (unit)Gy/25f （1.8Gy/f/d，5 f/w） | Drug: Trastuzumab<br>* intravenously administered with the loading dose of 8 mg/kg followed by maintenance dose of 6mg/kg in day 1 of each cycle<br>Drug: Capecitabine<br>* 825 1000mg/m2 bid d1-14<br>Drug: Oxaliplatin<br>* 130 mg/m2 Ivgtt d1 q3w<br>Radiation: Radiotherapy<br>* 45 Gray (unit) Gy/25f （1.8Gy/f/d，5 f/w）<br>|
| Active Comparator: XELOX and radiotherapy<br>Capecitabine：825 1000mg/m2 bid d1-14，Oxaliplatin 130 mg/m2 Ivgtt d1 q3w Radiotherapy：45Gy/25f （1.8Gy/f/d，5 f/w） | Drug: Capecitabine<br>* 825 1000mg/m2 bid d1-14<br>Drug: Oxaliplatin<br>* 130 mg/m2 Ivgtt d1 q3w<br>Radiation: Radiotherapy<br>* 45 Gray (unit) Gy/25f （1.8Gy/f/d，5 f/w）<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The pathological complete response rate(pCR) | The lesion disappeared completely by pathology | within 3 weeks after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Baseline to measured date of death from any cause | 3 years | 
| Disease-free survival(DFS) | Baseline to measured date of recurrence or death from any cause | 3 years | 
| Disease Control Rate (DCR) | Percentage of participants who achieved a best overall response of CR or PR or Stable Disease (SD). | 3 years | 
| Percentage of Participants With Objective Response According to Modified Response Evaluation Criteria In Solid Tumors(mRECIST) v1.1 | Objective response referred to participants with complete response (CR) or partial response (PR). CR: disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR: greater than or equal to (>=) 30% decrease in sum of the longest diameter (LD) of all target lesions taking as reference the screening sum LD. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed no less than 4 weeks after the criteria for response were first met. Longer intervals as determined by the study protocol were also appropriate. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. | within 3 weeks after surgery | 
| Percentage of Participants With Clinically Significant Improvement in European Organisation for Research and Treatment of Cancer Quality of Life Core Module 30 (EORTC Quality of Life Questionnaire (QLQ)-C30) Score | The EORTC QLQ-C30 is a validated, cancer-specific 30-item patient-reported measure, and contains 14 domains to assess the impact of cancer treatment on 5 aspects of participants functioning (physical, role, cognitive, emotional, and social), 9 aspects of disease/treatment-related symptoms (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea) and a global QoL/overall health status scale. Questions used 4 point scale (1 'Not at all' to 4 'Very much'; with the exception of the QoL/health status scale which uses a 7-point scale (1 'very poor' to 7 'Excellent'). Each scale is transformed on a scale of 0-100; a higher score equals (=) a better level of functioning or greater degree of symptoms. Change of greater than or equal to (>=) 10-points has been found to be clinically significant. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. | Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at follow-up | 
| Adverse events | Toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.The number of Participants with adverse events will be recorded at each treatment visit. | 3 years |