FLOT vs. FLOT/Herceptin/Pertuzumab for Perioperative Therapy of HER-2 Expressing Gastric or GEJ Cancer

This is a multicenter, randomized, controlled, open-label study including patients with locally advanced adenocarcinoma of the stomach and GEJ scheduled to receive perioperative chemotherapy. According to centrally assessed HER-2 status: Patients with HER-2 positive tumors will receive FLOT +/- Herceptin / pertuzumab.

The scope of the phase II portion of the trial is to evaluate pathological response rates of either regimen assessed by a centralized pathology and define safety and tolerability.

Patients with locally advanced esophagogastric adenocarcinoma (i.e. cT2 any N or any T N-positive) with exclusion of distant metastases will be included in this trial.

Patients will be stratified by age (18-69 vs. ≥ 70), tumor site (GEJ vs. gastric) and clinical stage (T1/2 vs. 3/4 and N- vs. N+) and randomized 1:1 to receive either FLOT (Arm A) or FLOT/Herceptin/pertuzumab (Arm B).

Arm A (control group) Patients randomized to Arm A will receive 4 pre-operative treatments of FLOT (Docetaxel 50 mg/m², iv over 2 h; Oxaliplatin 85 mg/m² in 500 ml G5%, iv over 2h; Leucovorin 200 mg/m² in 250 ml NaCl 0.9 %, iv over 1 h; 5-FU 2600 mg/m², iv over 24 h) on d1, d15, d29, d43 of the preoperative treatment phase. Surgery is recommended to occur 4 weeks after last FLOT (4 weeks after d43 = day 71). Patients will receive 4 additional post-operative treatments of FLOT on d1, d15, d29, and d43 of the post-operative treatment phase. Post-operative treatment should start 6 to 8 weeks, but at maximum 12 weeks after surgery.

Arm B (Herceptin/pertuzumab group) Patients randomized to Arm B will receive the FLOT regimen identical to Arm A as described above in conjunction with three-weekly Herceptin at 8mg/kg initial dose (Day 1, loading dose) followed by subsequent doses of Herceptin at 6mg/kg on d22 and d43 and pertuzumab at 840mg on d1, d22, and d43. Surgery is recommended to occur 4 weeks after last FLOT/Herceptin/pertuzumab dose (4 weeks after d43 = day 71). Patients will receive 3 additional doses of Herceptin and pertuzumab on d1, d22, and d43 of the post-operative treatment phase, together with the postoperative chemotherapy. Moreover, patients will receive 11 additional doses of Herceptin and pertuzumab after the end of post-operative FLOT.

In both of the arms, tumor assessments (CT or MRI) are performed before randomization and prior to surgery and then every 3 months thereafter until progression/relapse, death or end of follow-up.

During treatment, clinical visits (blood cell counts, detection of toxicity) occur prior to every treatment dose. Safety of FLOT/Herceptin/pertuzumab will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported.

Inclusion criteria

• Histologically confirmed adenocarcinoma of the GEJ (type I-III) or the stomach (uT2, uT3, uT4, any N category, M0), or any T N+ M0 patient, with the following specifications:

• Medical and technical operability
• Centralized detection of either an adenocarcinoma with HER-2 3+ (IHC) or HER-2 2+ (IHC) with amplification proven by FISH, SISH or CISH
• No preceding cytotoxic or targeted therapy
• No prior partial or complete tumor resection
• Exclusion of the infiltration of any adjacent organs or structures by CT or MRI
• Exclusion of distant metastasis by CT or MRI of thorax and abdomen, and bone scan (if osseous lesions are suspected due to clinical signs)
• Female and male patients ≥ 18 years. Patients in reproductive age must be willing to use adequate contraception during the study and for 7 months after the end of pertuzumab and Herceptin treatment (Appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap)). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start.
• ECOG ≤ 2
• Laparoscopic exclusion of peritoneal carcinomatosis, if suspected clinically
• Adequate haematological, hepatic and renal function parameters:

• Leukocytes ≥ 3.000/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
• LVEF value > 55 %, as assessed by echocardiography
• Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures

Exclusion criteria

• Patients with involved retroperitoneal (e.g. para-aortal, paracaval or interaortocaval lymph nodes) or mesenterial lymph nodes (distant metastasis!)
• Known hypersensitivity against Herceptin, pertuzumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
• Other known contraindications against Herceptin, pertuzumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
• Documented history of congestive heart failure of any NYHA, myocardial infarction within the past 6 months before the first dose of study treatment
• Clinically significant valvular defect , history of poorly controlled arterial hypertension (systolic blood pressure > 180 mmHG or diastolic blood pressure > 100 mmHg) or uncontrollable high-risk cardiac arrhythmia (i.e tachycardia with a heart rate > 100/min at rest), significant ventricular arrhythmia (ventricular tachycardia) or higher grade atrioventricular-block (second degree AV-block Type 2 (Mobitz2) or third degree AV-block)
• 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
• Other severe internal disease or acute infection
• Peripheral polyneuropathy ≥ NCI Grade II
• Chronic inflammatory bowel disease
• Clinically significant active GI bleeding
• 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