Trastuzumab and Standard Treatment With Chemo- and Immunotherapy as First Line Treatment for HER2 Positive Esophageal Squamous Cell Carcinoma Patients

Study Overview
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Brief Summary
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The study aims to determine the efficacy of trastuzumab added to standard treatment (fluoropyrimidine/platinum doublet with pembrolizumab) in patients with HER2 positive Esophageal squamous cell carcinoma (ESCC) determined by 6 months progression free survival (PFS) (RECIST 1.1).

Official Title
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HERES Trial: Trastuzumab and Standard Treatment With Chemo- and Immunotherapy as First Line Treatment for HER2 Positive Esophageal Squamous Cell Carcinoma Patients

Conditions
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Esophageal Squamous Cell Carcinoma, HER-2 Protein Overexpression, HER-2 Gene Amplification

Intervention / Treatment
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* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Age ≥18 years Inoperable locally advanced or metastatic squamous cell carcinoma of the esophagus not amenable for curative intended therapy HER2 positive defined as IHC2+ and FISH amplification ratio ≥2 or IHC3+ ECOG PS <2 Baseline left ventricular ejection fraction > 50% measured by echocardiography or MUGA Adequate bone marrow function and organ function: Hematopoietic function: Leucocytes > 3.0 x 109/l, neutrocytes > 1.5 x 109/l and thrombocytes > 100 x 109/l Serum bilirubin < 1.5 × upper limit of normal (ULN); and AST/ALT < 2.5 × ULN (or < 5 × ULN in patients with liver metastases). Creatinine clearance > 30 ml/min Exclusion Criteria: Prior systemic treatment with non-curative intent including HER2-targeting drugs. Prior neoadjuvant and adjuvant therapies as well as palliative radiotherapy are allowed Significant medical illness that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate study treatment Congestive heart failure (New York Heart Association (NYHA) class 3+4); uncontrolled angina pectoris; poorly controlled hypertension (systolic BP > 180 mmHg or diastolic BP > 100 mmHg); or high-risk uncontrollable arrhythmias. Patients with severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy. Patients with known hypersensitivity to trastuzumab or any of the study drugs, murine proteins, or to any of the excipients Symptomatic brain metastases uncontrolled by corticosteroids or carcinomatous meningitis Homozygosity or compound heterozygosity for more than one gene variant of dihydropyrimidine dehydrogenase (DPD) known to cause major reduced metabolism of 5-FU derivates OR plasma uracil > 150 ng/ml are not eligible. Patients with minor DPD insufficiency are allowed provided that local guidelines for administration of 5-FU are followed. Any other cancer (excluding low risk prostate cancer, carcinoma in situ and radically operated localised squamous skin cancer) with clinical activity within the last 2 years Other current cancer treatments except for anti-hormone and anti-resorptive treatment of bone metastasis. Allopurinol, phenytoin, warfarin treatment is not allowed. Non vitamin K oral anticoagulants (NOAK) and low molecular weight (LMW) heparin is allowed Pregnancy or breast-feeding Positive serum pregnancy test in women of childbearing potential. Subjects with reproductive potential not willing to use an effective method of contraception under and 3 months after participation in this study

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Interventional Model Description: The study is a two-staged single arm national phase II trial Stage 1: 17 patients Stage 2: 7 patients
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br> | Drug: Trastuzumab<br>* Addition of trastuzumab to standard treatment (fluoropyrimidine/platinum doublet with pembrolizumab)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) . | PFS according to RECIST 1.1 | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate according to RECIST 1.1 | Partial, complete and overall response rate according to RECIST 1.1 | Best response during 6 months follow-up | 
| Frequency of AEs assessed by NCI CTCAE, v. 5.0 | Safety and tolerability of trastuzumab, pembrolizumab and a fluoropyrimidine/platinum assessed by NCI CTCAE, v. 5.0 | During minimum 6 months follow-up | 
| Overall survival | Time to death of all causes | 6 months |