HERES trial: Trastuzumab and standard treatment with chemo- and immunotherapy as first line treatment for HER2 positive esophageal squamous cell carcinoma patients

Prior treatment

• Prior systemic treatment with non-curative intent including HER2-targeting drugs. Prior neoadjuvant and adjuvant therapies as well as palliative radiotherapy are allowed
• Symptomatic brain metastases uncontrolled by corticosteroids or carcinomatous meningitis

Other illness

• 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
• 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.

Lab values

• Positive serum pregnancy test in women of childbearing potential

Other

• 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
• Subjects with reproductive potential not willing to use an effective method of contraception under and 3 months after participation in this study

• 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 either: a. IHC1+ and ISH positive (amplification ratio (HER2/CEP17) ≥ 2.0) and a high gene count fulfilling either: (HER2/cell) ≥ 6.0 or (HER2/cell) ≥ 4.0 assessed by two different ISH probes b. IHC2+ and ISH positive (ISH amplification ratio (HER2/CEP17) ≥ 2.0) c. IHC3+
  • ECOG PS <2
  • Baseline left ventricular ejection fraction > 50% measured by echocardiography or MUGA
  • Adequate bone marrow function and organ function: a. Leucocytes > 3.0 x 109/l, neutrocytes > 1.5 x 109/l and thrombocytes > 100 x 109/l b. Serum bilirubin < 1.5 × upper limit of normal (ULN); and AST/ALT < 2.5 × ULN (or < 5 × ULN in patients with liver metastases). c. Creatinine clearance > 30 ml/min