Explorative Phase II Study of Perioperative Treatment in Patients With Adenocarcinoma of the Gastroesophageal Junction or Stomach

Multicenter, Explorative Phase II Study of Perioperative 5-FU, Leucovorin, Docetaxel, and Oxaliplatin (FLOT) in Combination With Trastuzumab in Patients With HER2-positive, Locally Advanced, Resectable Adenocarcinoma of the Gastroesophageal Junction or Stomach (HerFLOT)

The purpose of this study is to determine the rate of complete pathological responses (percentage of patients with pCR referring to the total number of enrolled and eligible patients), as evaluated centrally by a reference pathologist.

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the gastroesophageal junction (AEG I-III) or the stomach (uT2, uT3, uT4, any N category, M0), or any T N+ M0 patient, with the following specifications: Endosonography and an esophageal-gastro-duodenoscopy; Categorization of gastroesophageal junction tumors according to the classification by Siewert (1987, cf. appendix 2)

• Detection of an adenocarcinoma with HER2 3+ (IHC) or HER2 2+ (IHC) with amplification proven by FISH, SISH or CISH by an accredited local pathologist (for quality assurance tumor samples have to be available for a subsequent central review)
• No preceding cytotoxic or targeted therapy
• Male and female patients aged ≥ 18 years. If able to reproduce, patients must be willing to use highly effective methods of contraception during treatment and for 6 months after the end of treatment (adequate: methods fulfilling the requirements of the Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals [CPMP/ICH/286/95 mod]). Female patients with reproductive ability must have performed a negative pregnancy test within 7 days of study entry.
• ECOG ≤ 2
• Exclusion of distant metastasis by CT of thorax and abdomen, bone scan or MRI (if osseous lesions are suspected due to clinical signs)
• Laparoscopic exclusion of peritoneal carcinomatosis, if suspected clinically
• Adequate haematological, hepatic and renal function parameters: Leukocytes ≥ 3000/mm³, platelets ≥ 100,000/mm3; Serum creatinine ≤ 1.5 x upper limit of normal, or GFR > 40 ml/min; Bilirubin ≤ 1.5 x upper limit of normal, AST and ALT ≤ 3.5 x upper limit of normal, alkaline phosphatase ≤ 6 x upper limit of normal
• Normal cardiac ejection fraction, as assessed by echocardiography
• Written patient consent form

Exclusion Criteria:

• Known hypersensitivity against trastuzumab, murine proteins, 5-FU, leucovorin, oxaliplatin or docetaxel
• Other known contraindications against trastuzumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
• Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA III-IV
• Clinically significant valvular defect
• Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix
• Known brain metastases
• Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy
• Other severe internal disease or acute infection
• Peripheral polyneuropathy > NCI Grade II
• Chronic inflammatory bowel disease
• On-treatment participation in another clinical study in the period 30 days prior to inclusion and during the study
• Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment
• Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
• Any other concurrent antineoplastic treatment including irradiation